@article {1000616, title = {Genome wide association studies of drug-resistance determinants.}, journal = {Trends in Parasitology}, volume = {33}, year = {2017}, pages = {214-230}, abstract = {

Population genetic strategies that leverage association, selection, and linkage have identified drug-resistant loci. However, challenges and limitations persist in identifying drug-resistance loci in malaria. In this review we discuss the genetic basis of drug resistance and the use of genome-wide association studies, complemented by selection and linkage studies, to identify and understand mechanisms of drug resistance and response. We also discuss the implications of nongenetic mechanisms of drug resistance recently reported in the literature, and present models of the interplay between nongenetic and genetic processes that contribute to the emergence of drug resistance. Throughout, we examine artemisinin resistance as an example to emphasize challenges in identifying phenotypes suitable for population genetic studies as well as complications due to multiple-factor drug resistance.

}, author = {Volkman, Sarah K and Herman, Jonathan and Lukens, Amanda K and Hartl, Daniel L} } @article {1000606, title = {Genetic relatedness analysis reveals the cotransmission of genetically related Plasmodium falciparum parasites in Thi{\`e}s, Senegal.}, journal = {Genome Medicine}, year = {2017}, abstract = {

As public health interventions drive parasite populations to elimination, genetic epidemiology models that incorporate population genomics can be powerful tools for evaluating the effectiveness of continued intervention. However, current genetic epidemiology models may not accurately simulate the population genetic profile of parasite populations, particularly with regard to polygenomic (multi-strain) infections. Current epidemiology models simulate polygenomic infections via superinfection (multiple mosquito bites), despite growing evidence that cotransmission (a single mosquito bite) may contribute to polygenomic infections.

}, author = {Wong, W. and Griggs, A.D. and Daniels, R. F. and Schaffner, S. F. and Ndiaye, D. and Bei, A.K. and Deme, A.B. and MacInnis, B. and Volkman, S. K. and Hartl, D. L. and Neafsey, D. E. and Wirth, D.F.} } @article {1001216, title = {A pivot mutation impedes reverse evolution across an adaptive landscape for drug resistance in Plasmodium vivax}, journal = {Malaria Journal }, year = {2016}, abstract = {

Background: The study of reverse evolution from resistant to susceptible phenotypes can reveal constraints on biological evolution, a topic for which evolutionary theory has relatively few general principles. The public health catastrophe of antimicrobial resistance in malaria has brought these constraints on evolution into a practical realm, with one proposed solution: withdrawing anti-malarial medication use in high resistance settings, built on the assumption that reverse evolution occurs readily enough that populations of pathogens may revert to their susceptible states. While past studies have suggested limits to reverse evolution, there have been few attempts to properly dissect its mechanistic constraints. Methods: Growth rates were determined from empirical data on the growth and resistance from a set of combinatorially complete set of mutants of a resistance protein (dihydrofolate reductase) in Plasmodium vivax, to construct reverse evolution trajectories. The fitness effects of individual mutations were calculated as a function of drug environment, revealing the magnitude of epistatic interactions between mutations and genetic backgrounds. Evolution across the landscape was simulated in two settings: starting from the population fixed for the quadruple mutant, and from a polymorphic population evenly distributed between double mutants. Results: A single mutation of large effect (S117N) serves as a pivot point for evolution to high resistance regions of the landscape. Through epistatic interactions with other mutations, this pivot creates an epistatic ratchet against reverse evolution towards the wild type ancestor, even in environments where the wild type is the most fit of all genotypes. This pivot mutation underlies the directional bias in evolution across the landscape, where evolution towards the ancestor is precluded across all examined drug concentrations from various starting points in the landscape. Conclusions: The presence of pivot mutations can dictate dynamics of evolution across adaptive landscape through epistatic interactions within a protein, leaving a population trapped on local fitness peaks in an adaptive landscape, unable to locate ancestral genotypes. This irreversibility suggests that the structure of an adaptive landscape for a resistance protein should be understood before considering resistance management strategies. This proposed mechanism for constraints on reverse evolution corroborates evidence from the field indicating that phenotypic reversal often occurs via compensatory mutation at sites independent of those associated with the forward evolution of resistance. Because of this, molecular methods that identify resistance patterns via single SNPs in resistance-associated markers might be missing signals for resistance and compensatory mutation throughout the genome. In these settings, whole genome sequencing efforts should be used to identify resistance patterns, and will likely reveal a more complicated genomic signature for resistance and susceptibility, especially in settings where anti-malarial medications have been used intermittently. Lastly, the findings suggest that, given their role in dictating the dynamics of evolution across the landscape, pivot mutations might serve as future targets for therapy. Electronic supplementary material The online version of this article (doi:10.1186/s12936-016-1090-3) contains supplementary material, which is available to authorized users.

}, author = {Ogbunugafor, C.B. and Hartl, D. L.} } @article {1001206, title = {Adaptive Landscape by Environment Interactions Dictate Evolutionary Dynamics in Models of Drug resistance}, journal = {PLOS Computational Biology}, year = {2016}, abstract = {

The adaptive landscape analogy has found practical use in recent years, as many have explored how their understanding can inform therapeutic strategies that subvert the evolution of drug resistance. A major barrier to applications of these concepts is a lack of detail concerning how the environment affects adaptive landscape topography, and consequently, the outcome of drug treatment. Here we combine empirical data, evolutionary theory, and computer simulations towards dissecting adaptive landscape by environment interactions for the evolution of drug resistance in two dimensions{\textemdash}drug concentration and drug type. We do so by studying the resistance mediated by Plasmodium falciparum dihydrofolate reductase (DHFR) to two related inhibitors{\textemdash}pyrimethamine and cycloguanil{\textemdash}across a breadth of drug concentrations. We first examine whether the adaptive landscapes for the two drugs are consistent with common definitions of cross-resistance. We then reconstruct all accessible pathways across the landscape, observing how their structure changes with drug environment. We offer a mechanism for non-linearity in the topography of accessible pathways by calculating of the interaction between mutation effects and drug environment, which reveals rampant patterns of epistasis. We then simulate evolution in several different drug environments to observe how these individual mutation effects (and patterns of epistasis) influence paths taken at evolutionary {\textquotedblleft}forks in the road{\textquotedblright} that dictate adaptive dynamics in silico. In doing so, we reveal how classic metrics like the IC50 and minimal inhibitory concentration (MIC) are dubious proxies for understanding how evolution will occur across drug environments. We also consider how the findings reveal ambiguities in the cross-resistance concept, as subtle differences in adaptive landscape topography between otherwise equivalent drugs can drive drastically different evolutionary outcomes. Summarizing, we discuss the results with regards to their basic contribution to the study of empirical adaptive landscapes, and in terms of how they inform new models for the evolution of drug resistance.

}, author = {Ogbunugafor, C.B. and Wylie, C.S and Diakite, I and Weinreich, D. M. and Hartl, D. L.} } @article {1001041, title = {Biophysical principles predict fitness landscapes of drug resistance}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {113}, year = {2016}, abstract = {

Fitness landscapes of drug resistance constitute powerful tools to elucidate mutational pathways of antibiotic escape. Here, we developed a predictive biophysics-based fitness landscape of trimethoprim (TMP) resistance for Escherichia coli dihydrofolate reductase (DHFR). We investigated the activity, binding, folding stability, and intracellular abundance for a complete set of combinatorial DHFR mutants made out of three key resistance mutations and extended this analysis to DHFR originated from Chlamydia muridarum and Listeria grayi. We found that the acquisition of TMP resistance via decreased drug affinity is limited by a trade-off in catalytic efficiency. Protein stability is concurrently affected by the resistant mutants, which precludes a precise description of fitness from a single molecular trait. Application of the kinetic flux theory provided an accurate model to predict resistance phenotypes (IC50) quantitatively from a unique combination of the in vitro protein molecular properties. Further, we found that a controlled modulation of the GroEL/ES chaperonins and Lon protease levels affects the intracellular steady-state concentration of DHFR in a mutation-specific manner, whereas IC50 is changed proportionally, as indeed predicted by the model. This unveils a molecular rationale for the pleiotropic role of the protein quality control machinery on the evolution of antibiotic resistance, which, as we illustrate here, may drastically confound the evolutionary outcome. These results provide a comprehensive quantitative genotype{\textendash}phenotype map for the essential enzyme that serves as an important target of antibiotic and anticancer therapies.

}, author = {Joao V. Rodrigues and Shimon Bershtein and Anna Li and Elena R. Lozovsky and Daniel L. Hartl and Shakhnovich, EugeneI.} } @article {1001026, title = {Neighboring genes for DNA-binding proteins rescue male sterility in Drosophila hybrids}, journal = {PNAS }, year = {2016}, abstract = {

Crosses between closely related animal species often result in male hybrids that are sterile, and the molecular and functional basis of genetic factors for hybrid male sterility is of great interest. Here, we report a molecular and functional analysis of HMS1, a region of 9.2 kb in chromosome 3 of Drosophila mauritiana, which results in virtually complete hybrid male sterility when homozygous in the genetic background of sibling species Drosophila simulans. The HMS1 region contains two strong candidate genes for the genetic incompatibility, agt and Taf1. Both encode unrelated DNA-binding proteins, agt for an alkyl-cysteine-S-alkyltransferase and Taf1 for a subunit of transcription factor TFIID that serves as a multifunctional transcriptional regulator. The contribution of each gene to hybrid male sterility was assessed by means of germ-line transformation, with constructs containing complete agt and Taf1 genomic sequences as well as various chimeric constructs. Both agt and Taf1 contribute about equally to HMS1 hybrid male sterility. Transgenes containing either locus rescue sterility in about one-half of the males, and among fertile males the number of offspring is in the normal range. This finding suggests compensatory proliferation of the rescued, nondysfunctional germ cells. Results with chimeric transgenes imply that the hybrid incompatibilities result from interactions among nucleotide differences residing along both agt and Taf1. Our results challenge a number of preliminary generalizations about the molecular and functional basis of hybrid male sterility, and strongly reinforce the role of DNA-binding proteins as a class of genes contributing to the maintenance of postzygotic reproductive isolation.

}, author = {Marjorie A. Lienard and Luciana O. Araipe and Daniel L. Hartl} } @article {1001021, title = {Genotypic Context and Epistasis in Individuals and Populations}, journal = {Cell}, volume = {166}, year = {2016}, pages = {279-287}, abstract = {

Genes encode components of coevolved and interconnected networks. The effect of genotype on phenotype therefore depends on genotypic context through gene interactions known as epistasis. Epistasis is important in predicting phenotype from genotype for an individual. It is also examined in population studies to identify genetic risk factors in complex traits and to predict evolution under selection. Paradoxically, the effects of genotypic context in individuals and populations are distinct and sometimes contradictory. We argue that predicting genotype from phenotype for individuals based on population studies is difficult and, especially in human genetics, likely to result in underestimating the effects of genotypic context.

}, author = {Timothy B. Sackton and Daniel L. Hartl} } @article {1001016, title = {Mosquito Vectors and the Globalization of Plasmodium falciparum Malaria}, journal = {Annual Reviews }, volume = {50}, year = {2016}, pages = {447-465}, abstract = {

Plasmodium falciparum malaria remains a devastating public health problem. Recent discoveries have shed light on the origin and evolution of Plasmodium parasites and their interactions with their vertebrate and mosquito hosts. P. falciparum malaria originated in Africa from a single horizontal transfer between an infected gorilla and a human, and became global as the result of human migration. Today, P. falciparum malaria is transmitted worldwide by more than 70 different anopheline mosquito species. Recent studies indicate that the mosquito immune system can be a barrier to malaria transmission and that the P. falciparum Pfs47 gene allows the parasite to evade mosquito immune detection. Here, we review the origin and globalization of P. falciparum and integrate this history with analysis of the biology, evolution, and dispersal of the main mosquito vectors. This new perspective broadens our understanding of P. falciparum population structure and the dispersal of important parasite genetic traits.

}, author = {Alvaro Molina-Cruz and Martine M. Zilversmit and Daniel E. Neafsey and Daniel L. Hartl and Carolina Barillas-Mury} } @article {1001011, title = {A New take on John Maynard Smith{\textquoteright}s Concept of Protein Space for Understanding Molecular Evolution.}, journal = {PLOS Computational Biology}, year = {2016}, abstract = {

}, author = {Ogbunugafor, C.B. and Hartl D.L.} } @article {1000636, title = {Genetic evidence that the Makira region is a hotspot of Plasmodium falciparum transmission in northeastern Madagascar. }, journal = {Malaria Journal}, year = {2016}, abstract = {

Background: Encouraging advances in the control of Plasmodium falciparum malaria have been observed across much of Africa in the past decade. However, regions of high relative prevalence and transmission that remain unaddressed or unrecognized provide a threat to this progress. Difficulties in identifying such localized hotspots include inadequate surveillance, especially in remote regions, and the cost and labor needed to produce direct estimates of transmission. Genetic data can provide a much-needed alternative to such empirical estimates, as the pattern of genetic variation within malaria parasite populations is indicative of the level of local transmission. Here, genetic data were used to provide the first empirical estimates of P. falciparum malaria prevalence and transmission dynamics for the rural, remote Makira region of northeastern Madagascar. Methods: Longitudinal surveys of a cohort of 698 total individuals (both sexes, 0{\textendash}74 years of age) were performed in two communities bordering the Makira Natural Park protected area. Rapid diagnostic tests, with confirmation by molecular methods, were used to estimate P. falciparum prevalence at three seasonal time points separated by 4-month intervals. Genomic loci in a panel of polymorphic, putatively neutral markers were genotyped for 94 P. falciparum infections and used to characterize genetic parameters known to correlate with transmission levels. Results: Overall, 27.8\% of individuals tested positive for P. falciparum over the 10-month course of the study, a rate approximately sevenfold higher than the countrywide average for Madagascar. Among those P. falciparum infections, a high level of genotypic diversity and a high frequency of polygenomic infections (68.1\%) were observed, providing a pattern consistent with high and stable transmission. Conclusions: Prevalence and genetic diversity data indicate that the Makira region is a hotspot of P. falciparum transmission in Madagascar. This suggests that the area should be highlighted for future interventions and that additional areas of high transmission may be present in ecologically similar regions nearby. Electronic supplementary material The online version of this article (doi:10.1186/s12936-016-1644-4) contains supplementary material, which is available to authorized users.

}, author = {Rice, Benjamin L and Golden, Christopher D and Anjaranirina, Evelin Jean Gasta and Botelho, Carolina Mastella and Vokman, Sarah K and Hartl, Daniel L} } @article {1001316, title = {The utility of genomic data for Plasmodium vivax population surveillance}, journal = {Pathogens and Global Health}, volume = {109}, year = {2015}, pages = {153-161}, abstract = {

Genetic polymorphisms identified from genomic sequencing can be used to track changes in parasite populations through time. Such tracking is particularly informative when applying control strategies and evaluating their effectiveness. Using genomic approaches may also enable improved ability to categorise populations and to stratify them according to the likely effectiveness of intervention. Clinical applications of genomic approaches also allow relapses to be classified according to reinfection or recrudescence. These tools can be used not only to assess the effectiveness of malaria interventions but also to appraise the strategies for malaria elimination.

Keywords: Plasmodium vivax, Malaria, Eradication, Elimination, Genotyping

}, author = {Rachel F. Daniels and Benjamin L. Rice and Noah M. Daniels and Sarah K. Volkman and Daniel L. Hartl} } @article {1001311, title = {Behavioral idiosyncrasy reveals genetic control of phenotypic variability}, journal = {PNAS }, year = {2015}, abstract = {

Quantitative genetics has primarily focused on describing genetic effects on trait means and largely ignored the effect of alternative alleles on trait variability, potentially missing an important axis of genetic variation contributing to phenotypic differences among individuals. To study the genetic effects on individual-to-individual phenotypic variability (or intragenotypic variability), we used Drosophila inbred lines and measured the spontaneous locomotor behavior of flies walking individually in Y-shaped mazes, focusing on variability in locomotor handedness, an assay optimized to measure variability. We discovered that some lines had consistently high levels of intragenotypic variability among individuals, whereas lines with low variability behaved as although they tossed a coin at each left/right turn decision. We demonstrate that the degree of variability is itself heritable. Using a genome-wide association study (GWAS) for the degree of intragenotypic variability as the phenotype across lines, we identified several genes expressed in the brain that affect variability in handedness without affecting the mean. One of these genes, Ten-a, implicates a neuropil in the central complex of the fly brain as influencing the magnitude of behavioral variability, a brain region involved in sensory integration and locomotor coordination. We validated these results using genetic deficiencies, null alleles, and inducible RNAi transgenes. Our study reveals the constellation of phenotypes that can arise from a single genotype and shows that different genetic backgrounds differ dramatically in their propensity for phenotypic variabililty. Because traditional mean-focused GWASs ignore the contribution of variability to overall phenotypic variation, current methods may miss important links between genotype and phenotype.

}, author = {Julien F. Ayroles and Sean M. Buchanan and Chelsea O{\textquoteright}Leary and Kyobi Skutt-Kakaria and Jennifer K. Grenier and Andrew G. Clark and Daniel L. Hartl and Benjamin L. de Bivort} } @article {1001296, title = {Methods to Increase the Sensitivity of High Resolution Melting Single Nucleotide Polymorphism Genotyping in Malaria}, journal = {Journal of Visualized Experiments}, year = {2015}, abstract = {

Despite decades of eradication efforts, malaria remains a global burden. Recent renewed interest in regional elimination and global eradication has been accompanied by increased genomic information about Plasmodium parasite species responsible for malaria, including characteristics of geographical populations as well as variations associated with reduced susceptibility to anti-malarial drugs. One common genetic variation, single-nucleotide polymorphisms (SNPs), offers attractive targets for parasite genotyping. These markers are useful not only for tracking drug resistance markers but also for tracking parasite populations using markers not under drug or other selective pressures. SNP genotyping methods offer the ability to track drug resistance as well as to fingerprint individual parasites for population surveillance, particularly in response to malaria control efforts in regions nearing elimination status. While informative SNPs have been identified that are agnostic to specific genotyping technologies, high-resolution melting (HRM) analysis is particularly suited to field-based studies. Compared to standard fluorescent-probe based methods that require individual SNPs in a single labeled probe and offer at best 10\% sensitivity to detect SNPs in samples that contain multiple genomes (polygenomic), HRM offers 2-5\% sensitivity. Modifications to HRM, such as blocked probes and asymmetric primer concentrations as well as optimization of amplification annealing temperatures to bias PCR towards amplification of the minor allele, further increase the sensitivity of HRM. While the sensitivity improvement depends on the specific assay, we have increased detection sensitivities to less than 1\% of the minor allele. In regions approaching malaria eradication, early detection of emerging or imported drug resistance is essential for prompt response. Similarly, the ability to detect polygenomic infections and differentiate imported parasite types from cryptic local reservoirs can inform control programs. This manuscript describes modifications to high resolution melting technology that further increase its sensitivity to identify polygenomic infections in patient samples.

}, author = {Daniels, Rachel and Hamilton, Elizabeth J and Durfee, Katelyn and Ndiaye, Daouda and Wirth, Dyann F and Hartl, Daniel L and Volkman, Sarah K} } @article {1001291, title = {Direct Gamete Sequencing Reveals No Evidence for Segregation Distortion in House Mouse Hybrids}, journal = {PLOS ONE}, year = {2015}, abstract = {

Understanding the molecular basis of species formation is an important goal in evolutionary genetics, and Dobzhansky-Muller incompatibilities are thought to be a common source of postzygotic reproductive isolation between closely related lineages. However, the evolutionary forces that lead to the accumulation of such incompatibilities between diverging taxa are poorly understood. Segregation distorters are believed to be an important source of Dobzhansky-Muller incompatibilities between hybridizing species of Drosophila as well as hybridizing crop plants, but it remains unclear if these selfish genetic elements contribute to reproductive isolation in other taxa. Here, we collected viable sperm from first-generation hybrid male progeny of Mus musculus castaneus and M. m. domesticus, two subspecies of rodent in the earliest stages of speciation. We then genotyped millions of single nucleotide polymorphisms in these gamete pools and tested for a skew in the frequency of parental alleles across the genome. We show that segregation distorters are not measurable contributors to observed infertility in these hybrid males, despite sufficient statistical power to detect even weak segregation distortion with our novel method. Thus, reduced hybrid male fertility in crosses between these nascent species is attributable to other evolutionary forces.

}, author = {Corbett-Detig, R. and E. Jacobs-Palmer and Hartl, D. L. and Hoekstra, H} } @article {539001, title = {COIL: a methodology for evaluating malarial complexity of infection using likelihood from single nucleotide polymorphism data}, journal = {Malar J}, volume = {14}, number = {1}, year = {2015}, note = {

Galinsky, Kevin, Valim, Clarissa, Salmier, Ariellede, de Thoisy, Benoit, Musset, Lise, Legrand, Eric, Faust, Aubrey, Baniecki, Mary Lynn, Ndiaye, Daouda, Daniels, Rachel F, Hartl, Daniel L, Sabeti, Pardis C, Wirth, Dyann, \ FVolkman, Sarah K, Neafsey, Daniel. E, ENG 2015/01/21 06:00 Malar J. 2015 Jan 19;14(1):4.

}, month = {Jan 19}, pages = {4}, abstract = {

BACKGROUND: Complex malaria infections are defined as those containing more than one genetically distinct lineage of Plasmodium parasite. Complexity of infection (COI) is a useful parameter to estimate from patient blood samples because it is associated with clinical outcome, epidemiology and disease transmission rate. This manuscript describes a method for estimating COI using likelihood, called COIL, from a panel of bi-allelic genotyping assays. METHODS: COIL assumes that distinct parasite lineages in complex infections are unrelated and that genotyped loci do not exhibit significant linkage disequilibrium. Using the population minor allele frequency (MAF) of the genotyped loci, COIL uses the binomial distribution to estimate the likelihood of a COI level given the prevalence of observed monomorphic or polymorphic genotypes within each sample. RESULTS: COIL reliably estimates COI up to a level of three or five with at least 24 or 96 unlinked genotyped loci, respectively, as determined by in silico simulation and empirical validation. Evaluation of COI levels greater than five in patient samples may require a very large collection of genotype data, making sequencing a more cost-effective approach for evaluating COI under conditions when disease transmission is extremely high. Performance of the method is positively correlated with the MAF of the genotyped loci. COI estimates from existing SNP genotype datasets create a more detailed portrait of disease than analyses based simply on the number of polymorphic genotypes observed within samples. CONCLUSIONS: The capacity to reliably estimate COI from a genome-wide panel of SNP genotypes provides a potentially more accurate alternative to methods relying on PCR amplification of a small number of loci for estimating COI. This approach will also increase the number of applications of SNP genotype data, providing additional motivation to employ SNP barcodes for studies of disease epidemiology or control measure efficacy. The COIL program is available for download from GitHub, and users may also upload their SNP genotype data to a web interface for simple and efficient determination of sample COI.

}, isbn = {1475-2875 (Electronic)1475-2875 (Linking)}, author = {Galinsky, K. and Valim, C. and Salmier, A. and de Thoisy, B. and Musset, L. and Legrand, E. and Faust, A. and Baniecki, M. L. and Ndiaye, D. and Daniels, R. F. and Hartl, D. L. and Sabeti, P. C. and Wirth, DF and Volkman, S. K. and Neafsey, D. E.} } @article {538801, title = {Recurrent bottlenecks in the malaria life cycle obscure signals of positive selection}, journal = {Parasitology}, volume = {142 Suppl 1}, year = {2015}, note = {

Chang, Hsiao-HanHartl, Daniel LengU54 GM088558/GM/NIGMS NIH HHS/England2014/02/25 06:00Parasitology. 2015 Feb;142 Suppl 1:S98-S107. doi: 10.1017/S0031182014000067. Epub 2014 Feb 20.

}, month = {Feb}, pages = {S98-S107}, abstract = {

SUMMARY Detecting signals of selection in the genome of malaria parasites is a key to identify targets for drug and vaccine development. Malaria parasites have a unique life cycle alternating between vector and host organism with a population bottleneck at each transition. These recurrent bottlenecks could influence the patterns of genetic diversity and the power of existing population genetic tools to identify sites under positive selection. We therefore simulated the site-frequency spectrum of a beneficial mutant allele through time under the malaria life cycle. We investigated the power of current population genetic methods to detect positive selection based on the site-frequency spectrum as well as temporal changes in allele frequency. We found that a within-host selective advantage is difficult to detect using these methods. Although a between-host transmission advantage could be detected, the power is decreased when compared with the classical Wright-Fisher (WF) population model. Using an adjusted null site-frequency spectrum that takes the malaria life cycle into account, the power of tests based on the site-frequency spectrum to detect positive selection is greatly improved. Our study demonstrates the importance of considering the life cycle in genetic analysis, especially in parasites with complex life cycles.

}, isbn = {1469-8161 (Electronic)0031-1820 (Linking)}, author = {Chang, H. H. and Hartl, D. L.} } @article {539801, title = {Clonal Outbreak of Plasmodium falciparum Infection in Eastern Panama}, journal = {J Infect Dis}, year = {2014}, note = {

Obaldia, Nicanor 3rdBaro, Nicholas KCalzada, Jose ESantamaria, Ana MDaniels, RachelWong, WesleyChang, Hsiao-HanHamilton, Elizabeth JArevalo-Herrera, MyriamHerrera, SocratesWirth, Dyann FHartl, Daniel LMarti, MatthiasVolkman, Sarah KENGR01 AI106734/AI/NIAID NIH HHS/2014/10/23 06:00J Infect Dis. 2014 Oct 21. pii: jiu575.

}, month = {Oct 21}, abstract = {

Identifying the source of resurgent parasites is paramount to a strategic, successful intervention for malaria elimination. Although the malaria incidence in Panama is low, a recent outbreak resulted in a 6-fold increase in reported cases. We hypothesized that parasites sampled from this epidemic might be related and exhibit a clonal population structure. We tested the genetic relatedness of parasites, using informative single-nucleotide polymorphisms and drug resistance loci. We found that parasites were clustered into 3 clonal subpopulations and were related to parasites from Colombia. Two clusters of Panamanian parasites shared identical drug resistance haplotypes, and all clusters shared a chloroquine-resistance genotype matching the pfcrt haplotype of Colombian origin. Our findings suggest these resurgent parasite populations are highly clonal and that the high clonality likely resulted from epidemic expansion of imported or vestigial cases. Malaria outbreak investigations that use genetic tools can illuminate potential sources of epidemic malaria and guide strategies to prevent further resurgence in areas where malaria has been eliminated.

}, isbn = {1537-6613 (Electronic)0022-1899 (Linking)}, author = {Obaldia, N., 3rd and Baro, N. K. and Calzada, J. E. and Santamaria, A. M. and Daniels, R. and Wong, W. and Chang, H. H. and Hamilton, E. J. and Arevalo-Herrera, M. and Herrera, S. and Wirth, DF and Hartl, D. L. and Marti, M. and Volkman, S. K.} } @article {539551, title = {Genome-wide gene expression effects of sex chromosome imprinting in Drosophila}, journal = {G3 (Bethesda)}, volume = {4}, number = {1}, year = {2014}, note = {

Lemos, BernardoBranco, Alan TJiang, Pan-PanHartl, Daniel LMeiklejohn, Colin DengF32 GM72399/GM/NIGMS NIH HHS/GM065169/GM/NIGMS NIH HHS/GM079536/GM/NIGMS NIH HHS/Research Support, N.I.H., ExtramuralResearch Support, U.S. Gov{\textquoteright}t, Non-P.H.S.Bethesda, Md.2013/12/10 06:00G3 (Bethesda). 2014 Jan 10;4(1):1-10. doi: 10.1534/g3.113.008029.

}, month = {Jan}, pages = {1-10}, abstract = {

Imprinting is well-documented in both plant and animal species. In Drosophila, the Y chromosome is differently modified when transmitted through the male and female germlines. Here, we report genome-wide gene expression effects resulting from reversed parent-of-origin of the X and Y chromosomes. We found that hundreds of genes are differentially expressed between adult male Drosophila melanogaster that differ in the maternal and paternal origin of the sex chromosomes. Many of the differentially regulated genes are expressed specifically in testis and midgut cells, suggesting that sex chromosome imprinting might globally impact gene expression in these tissues. In contrast, we observed much fewer Y-linked parent-of-origin effects on genome-wide gene expression in females carrying a Y chromosome, indicating that gene expression in females is less sensitive to sex chromosome parent-of-origin. Genes whose expression differs between females inheriting a maternal or paternal Y chromosome also show sex chromosome parent-of-origin effects in males, but the direction of the effects on gene expression (overexpression or underexpression) differ between the sexes. We suggest that passage of sex chromosome chromatin through male meiosis may be required for wild-type function in F1 progeny, whereas disruption of Y-chromosome function through passage in the female germline likely arises because the chromosome is not adapted to the female germline environment.

}, keywords = {*Gene Expression Regulation, *Genome, *Genomic Imprinting, *X Chromosome/genetics/metabolism, *Y Chromosome/genetics/metabolism, Animals, Chromatin/metabolism, Drosophila/*genetics, Female, Genotype, Intestines/metabolism, Male, Meiosis, Testis/metabolism}, isbn = {2160-1836 (Electronic)2160-1836 (Linking)}, author = {Lemos, B. and Branco, A. T. and Jiang, P. P. and Hartl, D. L. and Meiklejohn, C. D.} } @article {539661, title = {Harnessing evolutionary fitness in Plasmodium falciparum for drug discovery and suppressing resistance}, journal = {Proc Natl Acad Sci U S A}, volume = {111}, number = {2}, year = {2014}, note = {

Lukens, Amanda KRoss, Leila SaxbyHeidebrecht, RichardJavier Gamo, FranciscoLafuente-Monasterio, Maria JBooker, Michael LHartl, Daniel LWiegand, Roger CWirth, Dyann FengR01 AI093716/AI/NIAID NIH HHS/R01 AI093716-01A1/AI/NIAID NIH HHS/R01 AI099105/AI/NIAID NIH HHS/Research Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov{\textquoteright}t2014/01/02 06:00Proc Natl Acad Sci U S A. 2014 Jan 14;111(2):799-804. doi: 10.1073/pnas.1320886110. Epub 2013 Dec 31.

}, month = {Jan 14}, pages = {799-804}, abstract = {

Drug resistance emerges in an ecological context where fitness costs restrict the diversity of escape pathways. These pathways are targets for drug discovery, and here we demonstrate that we can identify small-molecule inhibitors that differentially target resistant parasites. Combining wild-type and mutant-type inhibitors may prevent the emergence of competitively viable resistance. We tested this hypothesis with a clinically derived chloroquine-resistant (CQ(r)) malaria parasite and with parasites derived by in vitro selection with Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors. We screened a chemical library against CQ(s) and CQ(r) lines and discovered a drug-like compound (IDI-3783) that was potent only in the CQ(r) line. Surprisingly, in vitro selection of Plasmodium falciparum resistant to IDI-3783 restored CQ sensitivity, thereby indicating that CQ might once again be useful as a malaria therapy. In parallel experiments, we selected P. falciparum lines resistant to structurally unrelated PfDHODH inhibitors (Genz-666136 and DSM74). Both selections yielded resistant lines with the same point mutation in PfDHODH:E182D. We discovered a compound (IDI-6273) more potent against E182D than wild-type parasites. Selection of the E182D mutant with IDI-6273 yielded a reversion to the wild-type protein sequence and phenotype although the nucleotide sequence was different. Importantly, selection with a combination of Genz-669178, a wild-type PfDHODH inhibitor, and IDI-6273, a mutant-selective PfDHODH inhibitor, did not yield resistant parasites. These two examples demonstrate that the compromise between resistance and evolutionary fitness can be exploited to design therapies that prevent the emergence and spread of resistant organisms.

}, keywords = {Analysis of Variance, Base Sequence, Chloroquine/*pharmacology, Drug Discovery/*methods, Drug Evaluation, Preclinical, Drug Resistance/*genetics, Genetic Fitness/*genetics, Genome/genetics, Malaria/*drug therapy, Molecular Sequence Data, Oxidoreductases Acting on CH-CH Group Donors/antagonists \& inhibitors/genetics, Plasmodium falciparum/*genetics, Point Mutation/genetics, Pyrimidines, Sequence Analysis, DNA, Small Molecule Libraries, Triazoles}, isbn = {1091-6490 (Electronic)0027-8424 (Linking)}, author = {Lukens, A. K. and Ross, L. S. and Heidebrecht, R. and Javier Gamo, F. and Lafuente-Monasterio, M. J. and Booker, M. L. and Hartl, D. L. and Wiegand, R. C. and Wirth, DF} } @article {539961, title = {Positive selection drives faster-Z evolution in silkmoths}, journal = {Evolution}, volume = {68}, number = {8}, year = {2014}, note = {

Sackton, Timothy BCorbett-Detig, Russell BNagaraju, JavaregowdaVaishna, LakshmiArunkumar, Kallare PHartl, Daniel LengGM065169/GM/NIGMS NIH HHS/GM084236/GM/NIGMS NIH HHS/R01 GM065169/GM/NIGMS NIH HHS/R01 GM084236/GM/NIGMS NIH HHS/Research Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov{\textquoteright}t2014/05/16 06:00Evolution. 2014 Aug;68(8):2331-42. doi: 10.1111/evo.12449. Epub 2014 Jun 6.

}, month = {Aug}, pages = {2331-42}, abstract = {

Genes linked to X or Z chromosomes, which are hemizygous in the heterogametic sex, are predicted to evolve at different rates than those on autosomes. This "faster-X effect" can arise either as a consequence of hemizygosity, which leads to more efficient selection for recessive beneficial mutations in the heterogametic sex, or as a consequence of reduced effective population size of the hemizygous chromosome, which leads to increased fixation of weakly deleterious mutations due to genetic drift. Empirical results to date suggest that, while the overall pattern across taxa is complicated, systems with male heterogamy show a faster-X effect attributable to more efficient selection, whereas the faster-Z effect in female-heterogametic taxa is attributable to increased drift. To test the generality of the faster-Z pattern seen in birds and snakes, we sequenced the genome of the lepidopteran silkmoth Bombyx huttoni. We show that silkmoths experience faster-Z evolution, but unlike in birds and snakes, the faster-Z effect appears to be attributable to more efficient positive selection. These results suggest that female heterogamy alone is unlikely to explain the reduced efficacy of selection on vertebrate Z chromosomes. It is likely that many factors, including differences in overall effective population size, influence Z chromosome evolution.

}, keywords = {*Evolution, Molecular, *Genome, Insect, *Selection, Genetic, Animals, Bombyx/*genetics, Chromosome Mapping, Codon, Female, Linear Models, Male, Sequence Analysis, DNA, Sex Chromosomes/*genetics}, isbn = {1558-5646 (Electronic)0014-3820 (Linking)}, author = {Sackton, T. B. and Corbett-Detig, RB and Nagaraju, J. and Vaishna, L. and Arunkumar, K. P. and Hartl, D. L.} } @article {539701, title = {The roles of cis- and trans-regulation in the evolution of regulatory incompatibilities and sexually dimorphic gene expression}, journal = {Genome Res}, volume = {24}, number = {1}, year = {2014}, note = {

Meiklejohn, Colin DCoolon, Joseph DHartl, Daniel LWittkopp, Patricia Jeng1F32-GM089009-01A1/GM/NIGMS NIH HHS/GM065169/GM/NIGMS NIH HHS/Research Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov{\textquoteright}tResearch Support, U.S. Gov{\textquoteright}t, Non-P.H.S.2013/09/18 06:00Genome Res. 2014 Jan;24(1):84-95. doi: 10.1101/gr.156414.113. Epub 2013 Sep 16.

}, month = {Jan}, pages = {84-95}, abstract = {

Evolutionary changes in gene expression underlie many aspects of phenotypic diversity within and among species. Understanding the genetic basis for evolved changes in gene expression is therefore an important component of a comprehensive understanding of the genetic basis of phenotypic evolution. Using interspecific introgression hybrids, we examined the genetic basis for divergence in genome-wide patterns of gene expression between Drosophila simulans and Drosophila mauritiana. We find that cis-regulatory and trans-regulatory divergences differ significantly in patterns of genetic architecture and evolution. The effects of cis-regulatory divergence are approximately additive in heterozygotes, quantitatively different between males and females, and well predicted by expression differences between the two parental species. In contrast, the effects of trans-regulatory divergence are associated with largely dominant introgressed alleles, have similar effects in the two sexes, and generate expression levels in hybrids outside the range of expression in both parental species. Although the effects of introgressed trans-regulatory alleles are similar in males and females, expression levels of the genes they regulate are sexually dimorphic between the parental D. simulans and D. mauritiana strains, suggesting that pure-species genotypes carry unlinked modifier alleles that increase sexual dimorphism in expression. Our results suggest that independent effects of cis-regulatory substitutions in males and females may favor their role in the evolution of sexually dimorphic phenotypes, and that trans-regulatory divergence is an important source of regulatory incompatibilities.

}, keywords = {*Evolution, Molecular, *Gene Expression Regulation, *Genome, Insect, *Regulatory Elements, Transcriptional, Alleles, Animals, Biological Evolution, Drosophila/*genetics, Female, Gene Expression Profiling, Hybridization, Genetic, Male, Models, Genetic, Organ Specificity, Sex Characteristics, Species Specificity}, isbn = {1549-5469 (Electronic)1088-9051 (Linking)}, author = {Meiklejohn, C. D. and Coolon, J. D. and Hartl, D. L. and Wittkopp, P. J.} } @article {539211, title = {What can we learn from fitness landscapes?}, journal = {Curr Opin Microbiol}, volume = {21}, year = {2014}, note = {

Hartl, Daniel LengAI106734/AI/NIAID NIH HHS/R01 AI106734/AI/NIAID NIH HHS/Research Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov{\textquoteright}tReviewEngland2014/12/03 06:00Curr Opin Microbiol. 2014 Oct;21:51-7. doi: 10.1016/j.mib.2014.08.001. Epub 2014 Oct 13.

}, month = {Oct}, pages = {51-7}, abstract = {

A combinatorially complete data set consists of studies of all possible combinations of a set of mutant sites in a gene or mutant alleles in a genome. Among the most robust conclusions from these studies is that epistasis between beneficial mutations often shows a pattern of diminishing returns, in which favorable mutations are less fit when combined than would be expected. Another robust inference is that the number of adaptive evolutionary paths is often limited to a relatively small fraction of the theoretical possibilities, owing largely to sign epistasis requiring evolutionary steps that would entail a decrease in fitness. Here we summarize these and other results while also examining issues that remain unresolved and future directions that seem promising.

}, isbn = {1879-0364 (Electronic)1369-5274 (Linking)}, author = {Hartl, D. L.} } @article {539416, title = {Accessible mutational trajectories for the evolution of pyrimethamine resistance in the malaria parasite Plasmodium vivax}, journal = {J Mol Evol}, volume = {77}, number = {3}, year = {2013}, note = {

Jiang, Pan-PanCorbett-Detig, Russell BHartl, Daniel LLozovsky, Elena RengResearch Support, Non-U.S. Gov{\textquoteright}tGermany2013/09/28 06:00J Mol Evol. 2013 Sep;77(3):81-91. doi: 10.1007/s00239-013-9582-z. Epub 2013 Sep 27.

}, month = {Sep}, pages = {81-91}, abstract = {

Antifolate antimalarials, such as pyrimethamine, have experienced a dramatic reduction in therapeutic efficacy as resistance has evolved in multiple malaria species. We present evidence from one such species, Plasmodium vivax, which has experienced sustained selection for pyrimethamine resistance at the dihydrofolate reductase (DHFR) locus since the 1970s. Using a transgenic Saccharomyces cerevisiae model expressing the P. vivax DHFR enzyme, we assayed growth rate and resistance of all 16 combinations of four DHFR amino acid substitutions. These substitutions were selected based on their known association with drug resistance, both in natural isolates and in laboratory settings, in the related malaria species P. falciparum. We observed a strong correlation between the resistance phenotypes for these 16 P. vivax alleles and previously observed resistance data for P. falciparum, which was surprising since nucleotide diversity levels and common polymorphic variants of DHFR differ between the two species. Similar results were observed when we expressed the P. vivax alleles in a transgenic bacterial system. This suggests common constraints on enzyme evolution in the orthologous DHFR proteins. The interplay of negative trade-offs between the evolution of novel resistance and compromised endogenous function varies at different drug dosages, and so too do the major trajectories for DHFR evolution. In simulations, it is only at very high drug dosages that the most resistant quadruple mutant DHFR allele is favored by selection. This is in agreement with common polymorphic DHFR data in P. vivax, from which this quadruple mutant is missing. We propose that clinical dosages of pyrimethamine may have historically been too low to select for the most resistant allele, or that the fitness cost of the most resistant allele was untenable without a compensatory mutation elsewhere in the genome.

}, keywords = {Alleles, Antimalarials/pharmacology, Drug Resistance/*genetics, Evolution, Molecular, Genetic Loci, Inhibitory Concentration 50, Mutation, Plasmodium vivax/*drug effects/*genetics, Pyrimethamine/*pharmacology, Saccharomyces cerevisiae/metabolism, Tetrahydrofolate Dehydrogenase/genetics}, isbn = {1432-1432 (Electronic)0022-2844 (Linking)}, author = {Jiang, P. P. and Corbett-Detig, RB and Hartl, D. L. and Lozovsky, E. R.} } @article {538641, title = {Chromatin-associated proteins HP1 and Mod(mdg4) modify Y-linked regulatory variation in the drosophila testis}, journal = {Genetics}, volume = {194}, number = {3}, year = {2013}, note = {

Branco, Alan THartl, Daniel LLemos, Bernardoeng2013/05/03 06:00Genetics. 2013 Jul;194(3):609-18. doi: 10.1534/genetics.113.150805. Epub 2013 May 1.

}, month = {Jul}, pages = {609-18}, abstract = {

Chromatin remodeling is crucial for gene regulation. Remodeling is often mediated through chemical modifications of the DNA template, DNA-associated proteins, and RNA-mediated processes. Y-linked regulatory variation (YRV) refers to the quantitative effects that polymorphic tracts of Y-linked chromatin exert on gene expression of X-linked and autosomal genes. Here we show that naturally occurring polymorphisms in the Drosophila melanogaster Y chromosome contribute disproportionally to gene expression variation in the testis. The variation is dependent on wild-type expression levels of mod(mdg4) as well as Su(var)205; the latter gene codes for heterochromatin protein 1 (HP1) in Drosophila. Testis-specific YRV is abolished in genotypes with heterozygous loss-of-function mutations for mod(mdg4) and Su(var)205 but not in similar experiments with JIL-1. Furthermore, the Y chromosome differentially regulates several ubiquitously expressed genes. The results highlight the requirement for wild-type dosage of Su(var)205 and mod(mdg4) in enabling naturally occurring Y-linked regulatory variation in the testis. The phenotypes that emerge in the context of wild-type levels of the HP1 and Mod(mdg4) proteins might be part of an adaptive response to the environment.

}, keywords = {Animals, Chromatin/genetics, Chromosomal Proteins, Non-Histone/*genetics, DNA-Binding Proteins, Drosophila melanogaster/*genetics/growth \& development, Drosophila Proteins/*genetics, Enhancer Elements, Genetic, Gene Expression Regulation, Developmental, Gene-Environment Interaction, Genes, Y-Linked, Heterozygote, Male, Mutation, Phenotype, Recombinant Proteins/genetics, Testis/*metabolism, Transcription Factors/*genetics, Y Chromosome/metabolism}, isbn = {1943-2631 (Electronic)0016-6731 (Linking)}, author = {Branco, A. T. and Hartl, D. L. and Lemos, B.} } @article {539741, title = {DNA-binding specificity changes in the evolution of forkhead transcription factors}, journal = {Proc Natl Acad Sci U S A}, volume = {110}, number = {30}, year = {2013}, note = {

Nakagawa, SoGisselbrecht, Stephen SRogers, Julia MHartl, Daniel LBulyk, Martha LengR01 HG003985/HG/NHGRI NIH HHS/T32 GM008313/GM/NIGMS NIH HHS/Research Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov{\textquoteright}t2013/07/10 06:00Proc Natl Acad Sci U S A. 2013 Jul 23;110(30):12349-54. doi: 10.1073/pnas.1310430110. Epub 2013 Jul 8.

}, month = {Jul 23}, pages = {12349-54}, abstract = {

The evolution of transcriptional regulatory networks entails the expansion and diversification of transcription factor (TF) families. The forkhead family of TFs, defined by a highly conserved winged helix DNA-binding domain (DBD), has diverged into dozens of subfamilies in animals, fungi, and related protists. We have used a combination of maximum-likelihood phylogenetic inference and independent, comprehensive functional assays of DNA-binding capacity to explore the evolution of DNA-binding specificity within the forkhead family. We present converging evidence that similar alternative sequence preferences have arisen repeatedly and independently in the course of forkhead evolution. The vast majority of DNA-binding specificity changes we observed are not explained by alterations in the known DNA-contacting amino acid residues conferring specificity for canonical forkhead binding sites. Intriguingly, we have found forkhead DBDs that retain the ability to bind very specifically to two completely distinct DNA sequence motifs. We propose an alternate specificity-determining mechanism whereby conformational rearrangements of the DBD broaden the spectrum of sequence motifs that a TF can recognize. DNA-binding bispecificity suggests a previously undescribed source of modularity and flexibility in gene regulation and may play an important role in the evolution of transcriptional regulatory networks.

}, keywords = {*Biological Evolution, Acanthamoeba castellanii/metabolism, Amino Acid Sequence, Animals, Binding Sites, DNA/*metabolism, Forkhead Transcription Factors/chemistry/classification/*metabolism, Mice, Models, Molecular, Molecular Sequence Data, Phylogeny, Sequence Homology, Amino Acid}, isbn = {1091-6490 (Electronic)0027-8424 (Linking)}, author = {Nakagawa, S. and Gisselbrecht, S. S. and Rogers, J. M. and Hartl, D. L. and Bulyk, M. L.} } @article {538851, title = {Genetic incompatibilities are widespread within species}, journal = {Nature}, volume = {504}, number = {7478}, year = {2013}, note = {

Corbett-Detig, Russell BZhou, JunClark, Andrew GHartl, Daniel LAyroles, Julien FengGM065169/GM/NIGMS NIH HHS/GM084236/GM/NIGMS NIH HHS/HD059060/HD/NICHD NIH HHS/Research Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov{\textquoteright}tEngland2013/11/08 06:00Nature. 2013 Dec 5;504(7478):135-7. doi: 10.1038/nature12678. Epub 2013 Nov 6.

}, month = {Dec 5}, pages = {135-7}, abstract = {

The importance of epistasis--non-additive interactions between alleles--in shaping population fitness has long been a controversial topic, hampered in part by lack of empirical evidence. Traditionally, epistasis is inferred on the basis of non-independence of genotypic values between loci for a given trait. However, epistasis for fitness should also have a genomic footprint. To capture this signal, we have developed a simple approach that relies on detecting genotype ratio distortion as a sign of epistasis, and we apply this method to a large panel of Drosophila melanogaster recombinant inbred lines. Here we confirm experimentally that instances of genotype ratio distortion represent loci with epistatic fitness effects; we conservatively estimate that any two haploid genomes in this study are expected to harbour 1.15 pairs of epistatically interacting alleles. This observation has important implications for speciation genetics, as it indicates that the raw material to drive reproductive isolation is segregating contemporaneously within species and does not necessarily require, as proposed by the Dobzhansky-Muller model, the emergence of incompatible mutations independently derived and fixed in allopatry. The relevance of our result extends beyond speciation, as it demonstrates that epistasis is widespread but that it may often go undetected owing to lack of statistical power or lack of genome-wide scope of the experiments.

}, keywords = {Alleles, Animals, Arabidopsis/genetics, Drosophila melanogaster/*genetics, Epistasis, Genetic/*genetics, Genetic Speciation, Genome/*genetics, Genotype, Mutation, Zea mays/genetics}, isbn = {1476-4687 (Electronic)0028-0836 (Linking)}, author = {Corbett-Detig, RB and Zhou, J. and Clark, A. G. and Hartl, D. L. and Ayroles, J. F.} } @article {538866, title = {Genetic surveillance detects both clonal and epidemic transmission of malaria following enhanced intervention in Senegal}, journal = {PLoS One}, volume = {8}, number = {4}, year = {2013}, note = {

Daniels, RachelChang, Hsiao-HanSene, Papa DiogoyePark, Danny CNeafsey, Daniel ESchaffner, Stephen FHamilton, Elizabeth JLukens, Amanda KVan Tyne, DariaMboup, SouleymaneSabeti, Pardis CNdiaye, DaoudaWirth, Dyann FHartl, Daniel LVolkman, Sarah Keng1R01AI075080-01A1/AI/NIAID NIH HHS/1R56AI082589/AI/NIAID NIH HHS/5R01GM061351/GM/NIGMS NIH HHS/D43TW001503/TW/FIC NIH HHS/R01 AI099105/AI/NIAID NIH HHS/T32 AI007535/AI/NIAID NIH HHS/T32 AI007638/AI/NIAID NIH HHS/Research Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov{\textquoteright}t2013/04/18 06:00PLoS One. 2013 Apr 4;8(4):e60780. doi: 10.1371/journal.pone.0060780. Print 2013.

}, pages = {e60780}, abstract = {

Using parasite genotyping tools, we screened patients with mild uncomplicated malaria seeking treatment at a clinic in Thies, Senegal, from 2006 to 2011. We identified a growing frequency of infections caused by genetically identical parasite strains, coincident with increased deployment of malaria control interventions and decreased malaria deaths. Parasite genotypes in some cases persisted clonally across dry seasons. The increase in frequency of genetically identical parasite strains corresponded with decrease in the probability of multiple infections. Further, these observations support evidence of both clonal and epidemic population structures. These data provide the first evidence of a temporal correlation between the appearance of identical parasite types and increased malaria control efforts in Africa, which here included distribution of insecticide treated nets (ITNs), use of rapid diagnostic tests (RDTs) for malaria detection, and deployment of artemisinin combination therapy (ACT). Our results imply that genetic surveillance can be used to evaluate the effectiveness of disease control strategies and assist a rational global malaria eradication campaign.

}, keywords = {DNA Barcoding, Taxonomic, Epidemics, Genetic Linkage, Genotype, Humans, Malaria, Falciparum/*epidemiology/prevention \& control/*transmission, Multilocus Sequence Typing, Plasmodium falciparum/*genetics, Population Density, Prevalence, Seasons, Senegal/epidemiology}, isbn = {1932-6203 (Electronic)1932-6203 (Linking)}, author = {Daniels, R. and Chang, H. H. and Sene, P. D. and Park, D. C. and Neafsey, D. E. and Schaffner, S. F. and Hamilton, E. J. and Lukens, A. K. and Van Tyne, D. and Mboup, S. and Sabeti, P. C. and Ndiaye, D. and Wirth, DF and Hartl, D. L. and Volkman, S. K.} } @article {538806, title = {Malaria life cycle intensifies both natural selection and random genetic drift}, journal = {Proc Natl Acad Sci U S A}, volume = {110}, number = {50}, year = {2013}, note = {

Chang, Hsiao-HanMoss, Eli LPark, Daniel JNdiaye, DaoudaMboup, SouleymaneVolkman, Sarah KSabeti, Pardis CWirth, Dyann FNeafsey, Daniel EHartl, Daniel LengAI099105/AI/NIAID NIH HHS/R01 AI099105/AI/NIAID NIH HHS/Research Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov{\textquoteright}t2013/11/22 06:00Proc Natl Acad Sci U S A. 2013 Dec 10;110(50):20129-34. doi: 10.1073/pnas.1319857110. Epub 2013 Nov 20.

}, month = {Dec 10}, pages = {20129-34}, abstract = {

Analysis of genome sequences of 159 isolates of Plasmodium falciparum from Senegal yields an extraordinarily high proportion (26.85\%) of protein-coding genes with the ratio of nonsynonymous to synonymous polymorphism greater than one. This proportion is much greater than observed in other organisms. Also unusual is that the site-frequency spectra of synonymous and nonsynonymous polymorphisms are virtually indistinguishable. We hypothesized that the complicated life cycle of malaria parasites might lead to qualitatively different population genetics from that predicted from the classical Wright-Fisher (WF) model, which assumes a single random-mating population with a finite and constant population size in an organism with nonoverlapping generations. This paper summarizes simulation studies of random genetic drift and selection in malaria parasites that take into account their unusual life history. Our results show that random genetic drift in the malaria life cycle is more pronounced than under the WF model. Paradoxically, the efficiency of purifying selection in the malaria life cycle is also greater than under WF, and the relative efficiency of positive selection varies according to conditions. Additionally, the site-frequency spectrum under neutrality is also more skewed toward low-frequency alleles than expected with WF. These results highlight the importance of considering the malaria life cycle when applying existing population genetic tools based on the WF model. The same caveat applies to other species with similarly complex life cycles.

}, keywords = {*Founder Effect, *Genetic Drift, *Models, Genetic, *Selection, Genetic, Computer Simulation, Gene Frequency, Genetics, Population, Plasmodium falciparum/*genetics/*physiology, Polymorphism, Single Nucleotide/genetics}, isbn = {1091-6490 (Electronic)0027-8424 (Linking)}, author = {Chang, H. H. and Moss, E. L. and Park, D. J. and Ndiaye, D. and Mboup, S. and Volkman, S. K. and Sabeti, P. C. and Wirth, DF and Neafsey, D. E. and Hartl, D. L.} } @article {539966, title = {Meta-analysis reveals that genes regulated by the Y chromosome in Drosophila melanogaster are preferentially localized to repressive chromatin}, journal = {Genome Biol Evol}, volume = {5}, number = {1}, year = {2013}, note = {

Sackton, Timothy BHartl, Daniel LengGM084236/GM/NIGMS NIH HHS/Meta-AnalysisResearch Support, N.I.H., ExtramuralEngland2013/01/15 06:00Genome Biol Evol. 2013;5(1):255-66. doi: 10.1093/gbe/evt005.

}, pages = {255-66}, abstract = {

The Drosophila Y chromosome is a degenerated, heterochromatic chromosome with few functional genes. Despite this, natural variation on the Y chromosome in D. melanogaster has substantial trans-acting effects on the regulation of X-linked and autosomal genes. It is not clear, however, whether these genes simply represent a random subset of the genome or whether specific functional properties are associated with susceptibility to regulation by Y-linked variation. Here, we present a meta-analysis of four previously published microarray studies of Y-linked regulatory variation (YRV) in D. melanogaster. We show that YRV genes are far from a random subset of the genome: They are more likely to be in repressive chromatin contexts, be expressed tissue specifically, and vary in expression within and between species than non-YRV genes. Furthermore, YRV genes are more likely to be associated with the nuclear lamina than non-YRV genes and are generally more likely to be close to each other in the nucleus (although not along chromosomes). Taken together, these results suggest that variation on the Y chromosome plays a role in modifying how the genome is distributed across chromatin compartments, either via changes in the distribution of DNA-binding proteins or via changes in the spatial arrangement of the genome in the nucleus.

}, keywords = {*Genes, Insect, Animals, Chromosomes, Insect/*genetics/metabolism, DNA-Binding Proteins/metabolism, Drosophila melanogaster/*genetics/metabolism, Gene Expression Profiling, Gene Expression Regulation, Genetic Variation, Heterochromatin/*genetics/metabolism, Oligonucleotide Array Sequence Analysis, Regulatory Elements, Transcriptional, Transcription, Genetic, Y Chromosome/*genetics/metabolism}, isbn = {1759-6653 (Electronic)1759-6653 (Linking)}, author = {Sackton, T. B. and Hartl, D. L.} } @article {538646, title = {Natural variation of the Y chromosome suppresses sex ratio distortion and modulates testis-specific gene expression in Drosophila simulans}, journal = {Heredity (Edinb)}, volume = {111}, number = {1}, year = {2013}, note = {

Branco, A TTao, YHartl, D LLemos, BengGM079536/GM/NIGMS NIH HHS/R01 GM065169/GM/NIGMS NIH HHS/R01 HD060679/HD/NICHD NIH HHS/Research Support, N.I.H., ExtramuralEngland2013/04/18 06:00Heredity (Edinb). 2013 Jul;111(1):8-15. doi: 10.1038/hdy.2013.5. Epub 2013 Apr 17.

}, month = {Jul}, pages = {8-15}, abstract = {

X-linked sex-ratio distorters that disrupt spermatogenesis can cause a deficiency in functional Y-bearing sperm and a female-biased sex ratio. Y-linked modifiers that restore a normal sex ratio might be abundant and favored when a X-linked distorter is present. Here we investigated natural variation of Y-linked suppressors of sex-ratio in the Winters systems and the ability of these chromosomes to modulate gene expression in Drosophila simulans. Seventy-eight Y chromosomes of worldwide origin were assayed for their resistance to the X-linked sex-ratio distorter gene Dox. Y chromosome diversity caused males to sire approximately 63\% to approximately 98\% female progeny. Genome-wide gene expression analysis revealed hundreds of genes differentially expressed between isogenic males with sensitive (high sex ratio) and resistant (low sex ratio) Y chromosomes from the same population. Although the expression of about 75\% of all testis-specific genes remained unchanged across Y chromosomes, a subset of post-meiotic genes was upregulated by resistant Y chromosomes. Conversely, a set of accessory gland-specific genes and mitochondrial genes were downregulated in males with resistant Y chromosomes. The D. simulans Y chromosome also modulated gene expression in XXY females in which the Y-linked protein-coding genes are not transcribed. The data suggest that the Y chromosome might exert its regulatory functions through epigenetic mechanisms that do not require the expression of protein-coding genes. The gene network that modulates sex ratio distortion by the Y chromosome is poorly understood, other than that it might include interactions with mitochondria and enriched for genes expressed in post-meiotic stages of spermatogenesis.

}, keywords = {*Down-Regulation, *Gene Expression Regulation, Animals, Chromosomes, Insect/*genetics/metabolism, Drosophila Proteins/*genetics/metabolism, Drosophila/*genetics/metabolism, Female, Male, Organ Specificity, Sex Ratio, Testis/metabolism, Y Chromosome/*genetics/metabolism}, isbn = {1365-2540 (Electronic)0018-067X (Linking)}, author = {Branco, A. T. and Tao, Y. and Hartl, D. L. and Lemos, B.} } @article {540166, title = {Rapidly evolving R genes in diverse grass species confer resistance to rice blast disease}, journal = {Proc Natl Acad Sci U S A}, volume = {110}, number = {46}, year = {2013}, note = {

Yang, SihaiLi, JingZhang, XiaohuiZhang, QijunHuang, JuChen, Jian-QunHartl, Daniel LTian, DachengengResearch Support, Non-U.S. Gov{\textquoteright}t2013/10/23 06:00Proc Natl Acad Sci U S A. 2013 Nov 12;110(46):18572-7. doi: 10.1073/pnas.1318211110. Epub 2013 Oct 21.

}, month = {Nov 12}, pages = {18572-7}, abstract = {

We show that the genomes of maize, sorghum, and brachypodium contain genes that, when transformed into rice, confer resistance to rice blast disease. The genes are resistance genes (R genes) that encode proteins with nucleotide-binding site (NBS) and leucine-rich repeat (LRR) domains (NBS-LRR proteins). By using criteria associated with rapid molecular evolution, we identified three rapidly evolving R-gene families in these species as well as in rice, and transformed a randomly chosen subset of these genes into rice strains known to be sensitive to rice blast disease caused by the fungus Magnaporthe oryzae. The transformed strains were then tested for sensitivity or resistance to 12 diverse strains of M. oryzae. A total of 15 functional blast R genes were identified among 60 NBS-LRR genes cloned from maize, sorghum, and brachypodium; and 13 blast R genes were obtained from 20 NBS-LRR paralogs in rice. These results show that abundant blast R genes occur not only within species but also among species, and that the R genes in the same rapidly evolving gene family can exhibit an effector response that confers resistance to rapidly evolving fungal pathogens. Neither conventional evolutionary conservation nor conventional evolutionary convergence supplies a satisfactory explanation of our findings. We suggest a unique mechanism termed "constrained divergence," in which R genes and pathogen effectors can follow only limited evolutionary pathways to increase fitness. Our results open avenues for R-gene identification that will help to elucidate R-gene vs. effector mechanisms and may yield new sources of durable pathogen resistance.

}, keywords = {*Evolution, Molecular, *Magnaporthe, Base Sequence, Brachypodium/genetics, China, Disease Resistance/*genetics, Genes, Plant/*genetics, Likelihood Functions, Models, Genetic, Molecular Sequence Data, Oryza sativa/genetics/*microbiology, Phylogeny, Plant Diseases/*microbiology, Real-Time Polymerase Chain Reaction, Sequence Analysis, DNA, Sorghum/genetics, Transformation, Genetic, Zea mays/genetics}, isbn = {1091-6490 (Electronic)0027-8424 (Linking)}, author = {Yang, S. and J. Li and Zhang, X. and Zhang, Q. and Huang, J. and Chen, J. Q. and Hartl, D. L. and Tian, D.} } @article {540146, title = {Application of genomics to field investigations of malaria by the international centers of excellence for malaria research}, journal = {Acta Trop}, volume = {121}, number = {3}, year = {2012}, note = {

Volkman, Sarah KNdiaye, DaoudaDiakite, MahamadouKoita, Ousmane ANwakanma, DavisDaniels, Rachel FPark, Daniel JNeafsey, Daniel EMuskavitch, Marc A TKrogstad, Donald JSabeti, Pardis CHartl, Daniel LWirth, Dyann FengMC_UP_A900_1117/Medical Research Council/United KingdomU19 AI089696/AI/NIAID NIH HHS/U19 AI089696-01/AI/NIAID NIH HHS/ReviewNetherlands2011/12/21 06:00Acta Trop. 2012 Mar;121(3):324-32. doi: 10.1016/j.actatropica.2011.12.002. Epub 2011 Dec 13.

}, month = {Mar}, pages = {324-32}, abstract = {

Success of the global research agenda toward eradication of malaria will depend on development of new tools, including drugs, vaccines, insecticides and diagnostics. Genomic information, now available for the malaria parasites, their mosquito vectors, and human host, can be leveraged to both develop these tools and monitor their effectiveness. Although knowledge of genomic sequences for the malaria parasites, Plasmodium falciparum and Plasmodium vivax, have helped advance our understanding of malaria biology, simply knowing this sequence information has not yielded a plethora of new interventions to reduce the burden of malaria. Here we review and provide specific examples of how genomic information has increased our knowledge of parasite biology, focusing on P. falciparum malaria. We then discuss how population genetics can be applied toward the epidemiological and transmission-related goals outlined by the International Centers of Excellence for Malaria Research groups recently established by the National Institutes of Health. Finally, we propose genomics is a research area that can promote coordination and collaboration between various ICEMR groups, and that working together as a community can significantly advance the value of this information toward reduction of the global malaria burden.

}, keywords = {*Genome, Protozoan, *Genomics, *International Cooperation, Animals, Disease Eradication/methods/organization \& administration, Disease Transmission, Infectious/prevention \& control, Genetic Markers, Genetic Variation, Humans, Insect Vectors/parasitology, Malaria, Falciparum/epidemiology/parasitology/*prevention \& control, Plasmodium falciparum/genetics/pathogenicity, Research Design, Research/*organization \& administration}, isbn = {1873-6254 (Electronic)0001-706X (Linking)}, author = {Volkman, S. K. and Ndiaye, D. and Diakite, M. and Koita, O. A. and Nwakanma, D. and Daniels, R. F. and Park, D. J. and Neafsey, D. E. and Muskavitch, M. A. and Krogstad, D. J. and Sabeti, P. C. and Hartl, D. L. and Wirth, DF} } @article {539941, title = {Chimeric genes as a source of rapid evolution in Drosophila melanogaster}, journal = {Mol Biol Evol}, volume = {29}, number = {2}, year = {2012}, note = {

Rogers, Rebekah LHartl, Daniel LengGM084236/GM/NIGMS NIH HHS/R01-GM065169/GM/NIGMS NIH HHS/Research Support, N.I.H., Extramural2011/07/21 06:00Mol Biol Evol. 2012 Feb;29(2):517-29. doi: 10.1093/molbev/msr184. Epub 2011 Jul 18.

}, month = {Feb}, pages = {517-29}, abstract = {

Chimeric genes form through the combination of portions of existing coding sequences to create a new open reading frame. These new genes can create novel protein structures that are likely to serve as a strong source of novelty upon which selection can act. We have identified 14 chimeric genes that formed through DNA-level mutations in Drosophila melanogaster, and we investigate expression profiles, domain structures, and population genetics for each of these genes to examine their potential to effect adaptive evolution. We find that chimeric gene formation commonly produces mid-domain breaks and unites portions of wholly unrelated peptides, creating novel protein structures that are entirely distinct from other constructs in the genome. These new genes are often involved in selective sweeps. We further find a disparity between chimeric genes that have recently formed and swept to fixation versus chimeric genes that have been preserved over long periods of time, suggesting that preservation and adaptation are distinct processes. Finally, we demonstrate that chimeric gene formation can produce qualitative expression changes that are difficult to mimic through duplicate gene formation, and that extremely young chimeric genes (d(S) \< 0.03) are more likely to be associated with selective sweeps than duplicate genes of the same age. Hence, chimeric genes can serve as an exceptional source of genetic novelty that can have a profound influence on adaptive evolution in D. melanogaster.

}, keywords = {*Evolution, Molecular, Adaptation, Biological, Animals, Biological Evolution, Drosophila melanogaster/*genetics, Gene Expression Profiling, Genes, Insect, Genetic Variation, Genetics, Population, Mutant Chimeric Proteins/*genetics, Mutation, Polymorphism, Single Nucleotide, Sequence Alignment, Sequence Analysis, RNA}, isbn = {1537-1719 (Electronic)0737-4038 (Linking)}, author = {Rogers, R. L. and Hartl, D. L.} } @article {540076, title = {Evolutionary paths to antibiotic resistance under dynamically sustained drug selection}, journal = {Nat Genet}, volume = {44}, number = {1}, year = {2012}, note = {

Toprak, ErdalVeres, AdrianMichel, Jean-BaptisteChait, RemyHartl, Daniel LKishony, RoyengAI057159/AI/NIAID NIH HHS/GM079536/GM/NIGMS NIH HHS/GM081617/GM/NIGMS NIH HHS/R01 GM081617/GM/NIGMS NIH HHS/Research Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov{\textquoteright}t2011/12/20 06:00Nat Genet. 2011 Dec 18;44(1):101-5. doi: 10.1038/ng.1034.

}, month = {Jan}, pages = {101-5}, abstract = {

Antibiotic resistance can evolve through the sequential accumulation of multiple mutations. To study such gradual evolution, we developed a selection device, the {\textquoteright}morbidostat{\textquoteright}, that continuously monitors bacterial growth and dynamically regulates drug concentrations, such that the evolving population is constantly challenged. We analyzed the evolution of resistance in Escherichia coli under selection with single drugs, including chloramphenicol, doxycycline and trimethoprim. Over a period of approximately 20 days, resistance levels increased dramatically, with parallel populations showing similar phenotypic trajectories. Whole-genome sequencing of the evolved strains identified mutations both specific to resistance to a particular drug and shared in resistance to multiple drugs. Chloramphenicol and doxycycline resistance evolved smoothly through diverse combinations of mutations in genes involved in translation, transcription and transport. In contrast, trimethoprim resistance evolved in a stepwise manner, through mutations restricted to the gene encoding the enzyme dihydrofolate reductase (DHFR). Sequencing of DHFR over the time course of the experiment showed that parallel populations evolved similar mutations and acquired them in a similar order.

}, keywords = {*Biological Evolution, *Selection, Genetic, Anti-Bacterial Agents/pharmacology, Bacteriological Techniques, Culture Media, DNA, Bacterial, Drug Resistance, Microbial/*genetics, Drug Resistance, Multiple, Escherichia coli/genetics/growth \& development, Mutation, Sequence Analysis, DNA, Tetrahydrofolate Dehydrogenase/genetics}, isbn = {1546-1718 (Electronic)1061-4036 (Linking)}, author = {Toprak, E. and Veres, A. and Michel, J. B. and Chait, R. and Hartl, D. L. and Kishony, R.} } @article {540171, title = {Functional evidence that a recently evolved Drosophila sperm-specific gene boosts sperm competition}, journal = {Proc Natl Acad Sci U S A}, volume = {109}, number = {6}, year = {2012}, note = {

Yeh, Shu-DanDo, TiffanieChan, CarolusCordova, AdrianaCarranza, FranciscoYamamoto, Eugene AAbbassi, MashyaGandasetiawan, Kania ALibrado, PabloDamia, ElisabettaDimitri, PatrizioRozas, JulioHartl, Daniel LRoote, JohnRanz, Jose MengBBS/B/07705/Biotechnology and Biological Sciences Research Council/United KingdomGM056647/GM/NIGMS NIH HHS/Research Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov{\textquoteright}tResearch Support, U.S. Gov{\textquoteright}t, Non-P.H.S.2012/02/07 06:00Proc Natl Acad Sci U S A. 2012 Feb 7;109(6):2043-8. doi: 10.1073/pnas.1121327109. Epub 2012 Jan 23.

}, month = {Feb 7}, pages = {2043-8}, abstract = {

In many species, both morphological and molecular traits related to sex and reproduction evolve faster in males than in females. Ultimately, rapid male evolution relies on the acquisition of genetic variation associated with differential reproductive success. Many newly evolved genes are associated with novel functions that might enhance male fitness. However, functional evidence of the adaptive role of recently originated genes in males is still lacking. The Sperm dynein intermediate chain multigene family, which encodes a Sperm dynein intermediate chain presumably involved in sperm motility, originated from complex genetic rearrangements in the lineage that leads to Drosophila melanogaster within the last 5.4 million years since its split from Drosophila simulans. We deleted all the members of this multigene family resident on the X chromosome of D. melanogaster by chromosome engineering and found that, although the deletion does not result in a reduction of progeny number, it impairs the competence of the sperm in the presence of sperm from wild-type males. Therefore, the Sperm dynein intermediate chain multigene family contributes to the differential reproductive success among males and illustrates precisely how quickly a new gene function can be incorporated into the genetic network of a species.

}, keywords = {*Evolution, Molecular, Animals, Drosophila melanogaster/*genetics, Female, Fertility/genetics, Genes, Insect/*genetics, Male, Multigene Family/genetics, Organ Specificity/genetics, Reproducibility of Results, Spermatozoa/*physiology}, isbn = {1091-6490 (Electronic)0027-8424 (Linking)}, author = {Yeh, S. D. and Do, T. and Chan, C. and Cordova, A. and Carranza, F. and Yamamoto, E. A. and Abbassi, M. and Gandasetiawan, K. A. and Librado, P. and Damia, E. and Dimitri, P. and Rozas, J. and Hartl, D. L. and Roote, J. and Ranz, J. M.} } @article {538811, title = {Genomic sequencing of Plasmodium falciparum malaria parasites from Senegal reveals the demographic history of the population}, journal = {Mol Biol Evol}, volume = {29}, number = {11}, year = {2012}, note = {

Chang, Hsiao-HanPark, Daniel JGalinsky, Kevin JSchaffner, Stephen FNdiaye, DaoudaNdir, OmarMboup, SouleymaneWiegand, Roger CVolkman, Sarah KSabeti, Pardis CWirth, Dyann FNeafsey, Daniel EHartl, Daniel Leng(D43TW001503/TW/FIC NIH HHS/1R01AI075080-01A1/AI/NIAID NIH HHS/1R56AI082589/AI/NIAID NIH HHS/5R01GM061351/GM/NIGMS NIH HHS/Research Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov{\textquoteright}tResearch Support, U.S. Gov{\textquoteright}t, Non-P.H.S.2012/06/27 06:00Mol Biol Evol. 2012 Nov;29(11):3427-39. doi: 10.1093/molbev/mss161. Epub 2012 Jun 24.

}, month = {Nov}, pages = {3427-39}, abstract = {

Malaria is a deadly disease that causes nearly one million deaths each year. To develop methods to control and eradicate malaria, it is important to understand the genetic basis of Plasmodium falciparum adaptations to antimalarial treatments and the human immune system while taking into account its demographic history. To study the demographic history and identify genes under selection more efficiently, we sequenced the complete genomes of 25 culture-adapted P. falciparum isolates from three sites in Senegal. We show that there is no significant population structure among these Senegal sampling sites. By fitting demographic models to the synonymous allele-frequency spectrum, we also estimated a major 60-fold population expansion of this parasite population approximately 20,000-40,000 years ago. Using inferred demographic history as a null model for coalescent simulation, we identified candidate genes under selection, including genes identified before, such as pfcrt and PfAMA1, as well as new candidate genes. Interestingly, we also found selection against G/C to A/T changes that offsets the large mutational bias toward A/T, and two unusual patterns: similar synonymous and nonsynonymous allele-frequency spectra, and 18\% of genes having a nonsynonymous-to-synonymous polymorphism ratio \>1.

}, keywords = {*Sequence Analysis, DNA, Animals, Base Composition/genetics, demography, Gene Frequency/genetics, Genes, Protozoan/genetics, Genetics, Population, Genome, Protozoan/*genetics, Humans, Linkage Disequilibrium/genetics, Malaria, Falciparum/genetics/*parasitology, Models, Genetic, Nucleotides/genetics, Parasites/*genetics/growth \& development, Plasmodium falciparum/*genetics/growth \& development, Polymorphism, Genetic, Selection, Genetic, Senegal}, isbn = {1537-1719 (Electronic)0737-4038 (Linking)}, author = {Chang, H. H. and Park, D. J. and Galinsky, K. J. and Schaffner, S. F. and Ndiaye, D. and Ndir, O. and Mboup, S. and Wiegand, R. C. and Volkman, S. K. and Sabeti, P. C. and Wirth, DF and Neafsey, D. E. and Hartl, D. L.} } @article {539896, title = {Novel genes from formation to function}, journal = {Int J Evol Biol}, volume = {2012}, year = {2012}, note = {

Ponce, RitaMartinsen, LeneVicente, Luis MHartl, Daniel Leng2012/07/20 06:00Int J Evol Biol. 2012;2012:821645. doi: 10.1155/2012/821645. Epub 2012 Jul 3.

}, pages = {821645}, abstract = {

The study of the evolution of novel genes generally focuses on the formation of new coding sequences. However, equally important in the evolution of novel functional genes are the formation of regulatory regions that allow the expression of the genes and the effects of the new genes in the organism as well. Herein, we discuss the current knowledge on the evolution of novel functional genes, and we examine in more detail the youngest genes discovered. We examine the existing data on a very recent and rapidly evolving cluster of duplicated genes, the Sdic gene cluster. This cluster of genes is an excellent model for the evolution of novel genes, as it is very recent and may still be in the process of evolving.

}, isbn = {2090-052X (Electronic)2090-052X (Linking)}, author = {Ponce, R. and Martinsen, L. and Vicente, L. M. and Hartl, D. L.} } @article {538846, title = {Population genomics of inversion polymorphisms in Drosophila melanogaster}, journal = {PLoS Genet}, volume = {8}, number = {12}, year = {2012}, note = {

Corbett-Detig, Russell BHartl, Daniel LengGM084236/GM/NIGMS NIH HHS/Research Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov{\textquoteright}t2013/01/04 06:00PLoS Genet. 2012;8(12):e1003056. doi: 10.1371/journal.pgen.1003056. Epub 2012 Dec 20.

}, pages = {e1003056}, abstract = {

Chromosomal inversions have been an enduring interest of population geneticists since their discovery in Drosophila melanogaster. Numerous lines of evidence suggest powerful selective pressures govern the distributions of polymorphic inversions, and these observations have spurred the development of many explanatory models. However, due to a paucity of nucleotide data, little progress has been made towards investigating selective hypotheses or towards inferring the genealogical histories of inversions, which can inform models of inversion evolution and suggest selective mechanisms. Here, we utilize population genomic data to address persisting gaps in our knowledge of D. melanogaster{\textquoteright}s inversions. We develop a method, termed Reference-Assisted Reassembly, to assemble unbiased, highly accurate sequences near inversion breakpoints, which we use to estimate the age and the geographic origins of polymorphic inversions. We find that inversions are young, and most are African in origin, which is consistent with the demography of the species. The data suggest that inversions interact with polymorphism not only in breakpoint regions but also chromosome-wide. Inversions remain differentiated at low levels from standard haplotypes even in regions that are distant from breakpoints. Although genetic exchange appears fairly extensive, we identify numerous regions that are qualitatively consistent with selective hypotheses. Finally, we show that In(1)Be, which we estimate to be approximately 60 years old (95\% CI 5.9 to 372.8 years), has likely achieved high frequency via sex-ratio segregation distortion in males. With deeper sampling, it will be possible to build on our inferences of inversion histories to rigorously test selective models-particularly those that postulate that inversions achieve a selective advantage through the maintenance of co-adapted allele complexes.

}, keywords = {*Metagenomics, *Polymorphism, Genetic, Animals, Base Sequence, Biological Evolution, Chromosome Inversion/*genetics, Drosophila melanogaster/*genetics, Female, Haplotypes, Linkage Disequilibrium, Male, Selection, Genetic, Sequence Analysis, DNA}, isbn = {1553-7404 (Electronic)1553-7390 (Linking)}, author = {Corbett-Detig, RB and Hartl, D. L.} } @article {539831, title = {Sequence-based association and selection scans identify drug resistance loci in the Plasmodium falciparum malaria parasite}, journal = {Proc Natl Acad Sci U S A}, volume = {109}, number = {32}, year = {2012}, note = {

Park, Daniel JLukens, Amanda KNeafsey, Daniel ESchaffner, Stephen FChang, Hsiao-HanValim, ClarissaRibacke, UlfVan Tyne, DariaGalinsky, KevinGalligan, MeghanBecker, Justin SNdiaye, DaoudaMboup, SouleymaneWiegand, Roger CHartl, Daniel LSabeti, Pardis CWirth, Dyann FVolkman, Sarah Keng1R01AI075080-01A1/AI/NIAID NIH HHS/T32 AI007638/AI/NIAID NIH HHS/Research Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov{\textquoteright}tResearch Support, U.S. Gov{\textquoteright}t, Non-P.H.S.2012/07/25 06:00Proc Natl Acad Sci U S A. 2012 Aug 7;109(32):13052-7. doi: 10.1073/pnas.1210585109. Epub 2012 Jul 23.

}, month = {Aug 7}, pages = {13052-7}, abstract = {

Through rapid genetic adaptation and natural selection, the Plasmodium falciparum parasite--the deadliest of those that cause malaria--is able to develop resistance to antimalarial drugs, thwarting present efforts to control it. Genome-wide association studies (GWAS) provide a critical hypothesis-generating tool for understanding how this occurs. However, in P. falciparum, the limited amount of linkage disequilibrium hinders the power of traditional array-based GWAS. Here, we demonstrate the feasibility and power improvements gained by using whole-genome sequencing for association studies. We analyzed data from 45 Senegalese parasites and identified genetic changes associated with the parasites{\textquoteright} in vitro response to 12 different antimalarials. To further increase statistical power, we adapted a common test for natural selection, XP-EHH (cross-population extended haplotype homozygosity), and used it to identify genomic regions associated with resistance to drugs. Using this sequence-based approach and the combination of association and selection-based tests, we detected several loci associated with drug resistance. These loci included the previously known signals at pfcrt, dhfr, and pfmdr1, as well as many genes not previously implicated in drug-resistance roles, including genes in the ubiquitination pathway. Based on the success of the analysis presented in this study, and on the demonstrated shortcomings of array-based approaches, we argue for a complete transition to sequence-based GWAS for small, low linkage-disequilibrium genomes like that of P. falciparum.

}, keywords = {*Selection, Genetic, Base Sequence, Drug Resistance/*genetics, Gene Frequency, Genetic Loci/*genetics, Genome-Wide Association Study/*methods, Genotype, Linkage Disequilibrium, Molecular Sequence Data, Plasmodium falciparum/*genetics, Principal Component Analysis, Senegal, Sequence Analysis, DNA/methods}, isbn = {1091-6490 (Electronic)0027-8424 (Linking)}, author = {Park, D. J. and Lukens, A. K. and Neafsey, D. E. and Schaffner, S. F. and Chang, H. H. and Valim, C. and Ribacke, U and Van Tyne, D. and Galinsky, K. and Galligan, M. and Becker, J.S. and Ndiaye, D. and Mboup, S. and Wiegand, R. C. and Hartl, D. L. and Sabeti, P. C. and Wirth, DF and Volkman, S. K.} } @article {540181, title = {Y chromosome mediates ribosomal DNA silencing and modulates the chromatin state in Drosophila}, journal = {Proc Natl Acad Sci U S A}, volume = {109}, number = {25}, year = {2012}, note = {

Zhou, JunSackton, Timothy BMartinsen, LeneLemos, BernardoEickbush, Thomas HHartl, Daniel LengGM042790/GM/NIGMS NIH HHS/GM084236/GM/NIGMS NIH HHS/Research Support, N.I.H., Extramural2012/06/06 06:00Proc Natl Acad Sci U S A. 2012 Jun 19;109(25):9941-6. doi: 10.1073/pnas.1207367109. Epub 2012 Jun 4.

}, month = {Jun 19}, pages = {9941-6}, abstract = {

Although the Drosophila Y chromosome is degenerated, heterochromatic, and contains few genes, increasing evidence suggests that it plays an important role in regulating the expression of numerous autosomal and X-linked genes. Here we use 15 Y chromosomes originating from a single founder 550 generations ago to study the role of the Y chromosome in regulating rRNA gene transcription, position-effect variegation (PEV), and the link among rDNA copy number, global gene expression, and chromatin regulation. Based on patterns of rRNA gene transcription indicated by transcription of the retrotransposon R2 that specifically inserts into the 28S rRNA gene, we show that X-linked rDNA is silenced in males. The silencing of X-linked rDNA expression by the Y chromosome is consistent across populations and independent of genetic background. These Y chromosomes also vary more than threefold in rDNA locus size and cause dramatically different levels of PEV suppression. The degree of suppression is negatively associated with the number and fraction of rDNA units without transposon insertions, but not with total rDNA locus size. Gene expression profiling revealed hundreds of differentially expressed genes among these Y chromosome introgression lines, as well as a divergent global gene expression pattern between the low-PEV and high-PEV flies. Our findings suggest that the Y chromosome is involved in diverse phenomena related to transcriptional regulation including X-linked rDNA silencing and suppression of PEV phenotype. These results further expand our understanding of the role of the Y chromosome in modulating global gene expression, and suggest a link with modifications of the chromatin state.

}, keywords = {*Y Chromosome, Animals, Base Sequence, Chromatin/*genetics, DNA Primers, DNA, Ribosomal/*genetics, Drosophila/*genetics, Male, Polymerase Chain Reaction}, isbn = {1091-6490 (Electronic)0027-8424 (Linking)}, author = {Zhou, J. and Sackton, T. B. and Martinsen, L. and Lemos, B. and Eickbush, T. H. and Hartl, D. L.} } @article {540176, title = {Copy-number variation: the balance between gene dosage and expression in Drosophila melanogaster}, journal = {Genome Biol Evol}, volume = {3}, year = {2011}, note = {

Zhou, JunLemos, BernardoDopman, Erik BHartl, Daniel LengGM065169/GM/NIGMS NIH HHS/GM084236/GM/NIGMS NIH HHS/R01 GM084236/GM/NIGMS NIH HHS/R01 GM084236-03/GM/NIGMS NIH HHS/Research Support, N.I.H., ExtramuralEngland2011/10/08 06:00Genome Biol Evol. 2011;3:1014-24. doi: 10.1093/gbe/evr023.

}, pages = {1014-24}, abstract = {

Copy-number variants (CNVs) reshape gene structure, modulate gene expression, and contribute to significant phenotypic variation. Previous studies have revealed CNV patterns in natural populations of Drosophila melanogaster and suggested that selection and mutational bias shape genomic patterns of CNV. Although previous CNV studies focused on heterogeneous strains, here, we established a number of second-chromosome substitution lines to uncover CNV characteristics when homozygous. The percentage of genes harboring CNVs is higher than found in previous studies. More CNVs are detected in homozygous than heterozygous substitution strains, suggesting the comparative genomic hybridization arrays underestimate CNV owing to heterozygous masking. We incorporated previous gene expression data collected from some of the same substitution lines to investigate relationships between CNV gene dosage and expression. Most genes present in CNVs show no evidence of increased or diminished transcription, and the fraction of such dosage-insensitive CNVs is greater in heterozygotes. More than 70\% of the dosage-sensitive CNVs are recessive with undetectable effects on transcription in heterozygotes. A deficiency of singletons in recessive dosage-sensitive CNVs supports the hypothesis that most CNVs are subject to negative selection. On the other hand, relaxed purifying selection might account for the higher number of protein-protein interactions in dosage-insensitive CNVs than in dosage-sensitive CNVs. Dosage-sensitive CNVs that are upregulated and downregulated coincide with copy-number increases and decreases. Our results help clarify the relation between CNV dosage and gene expression in the D. melanogaster genome.

}, keywords = {*DNA Copy Number Variations, *Gene Dosage, Alleles, Animals, Comparative Genomic Hybridization/*methods, Databases, Genetic, DNA/isolation \& purification, Down-Regulation, Drosophila melanogaster/*genetics, Gene Expression, Gene Frequency, Heterozygote, Homozygote, Oligonucleotide Array Sequence Analysis/methods, Reproducibility of Results, Up-Regulation}, isbn = {1759-6653 (Electronic)1759-6653 (Linking)}, author = {Zhou, J. and Lemos, B. and Dopman, E. B. and Hartl, D. L.} } @article {538861, title = {The evolutionary landscape of antifolate resistance in Plasmodium falciparum}, journal = {J Genet}, volume = {90}, number = {2}, year = {2011}, note = {

Costanzo, Marna SHartl, Daniel LengGM079536/GM/NIGMS NIH HHS/R01 GM079536/GM/NIGMS NIH HHS/R01 GM079536-04/GM/NIGMS NIH HHS/R01 GM084236/GM/NIGMS NIH HHS/R01 GM084236-02/GM/NIGMS NIH HHS/Research Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov{\textquoteright}tReviewIndia2011/08/27 06:00J Genet. 2011 Aug;90(2):187-90.

}, month = {Aug}, pages = {187-90}, abstract = {

Resistance to antifolates in Plasmodium falciparum is well described and has been observed in clinical settings for decades. At the molecular level, point mutations in the dhfr gene that lead to resistance have been identified, and the crystal structure of the wildtype and mutant dihydrofolate reductase enzymes have been solved in complex with native substrate and drugs. However, we are only beginning to understand the complexities of the evolutionary pressures that lead to the evolution of drug resistance in this system. Microbial systems that allow heterologous expression of malarial proteins provide a tractable way to investigate patterns of evolution that can inform our eventual understanding of the more complex factors that influence the evolution of drug resistance in clinical settings. In this paper we will review work in Escherichia coli and Saccharomyces cerevisiae expression systems that explore the fitness landscape of mutations implicated in drug resistance and show that (i) a limited number of evolutionary pathways to resistance are followed with high probability; (ii) fitness costs associated with the maintenance of high levels of resistance are modest; and (iii) different antifolates may exert opposing selective forces.

}, keywords = {*Evolution, Molecular, Adaptation, Biological, Animals, Drug Resistance/*genetics, Folic Acid Antagonists/*pharmacology, Humans, Malaria, Falciparum/*drug therapy, Mutation, Plasmodium falciparum/drug effects/*genetics, Protozoan Proteins/genetics, Tetrahydrofolate Dehydrogenase/genetics}, isbn = {0973-7731 (Electronic)0022-1333 (Linking)}, author = {Costanzo, M. S. and Hartl, D. L.} } @article {538856, title = {Fitness trade-offs in the evolution of dihydrofolate reductase and drug resistance in Plasmodium falciparum}, journal = {PLoS One}, volume = {6}, number = {5}, year = {2011}, note = {

Costanzo, Marna SBrown, Kyle MHartl, Daniel LengGM079536/GM/NIGMS NIH HHS/Research Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov{\textquoteright}tResearch Support, U.S. Gov{\textquoteright}t, Non-P.H.S.2011/06/01 06:00PLoS One. 2011;6(5):e19636. doi: 10.1371/journal.pone.0019636. Epub 2011 May 23.

}, pages = {e19636}, abstract = {

BACKGROUND: Patterns of emerging drug resistance reflect the underlying adaptive landscapes for specific drugs. In Plasmodium falciparum, the parasite that causes the most serious form of malaria, antifolate drugs inhibit the function of essential enzymes in the folate pathway. However, a handful of mutations in the gene coding for one such enzyme, dihydrofolate reductase, confer drug resistance. Understanding how evolution proceeds from drug susceptibility to drug resistance is critical if new antifolate treatments are to have sustained usefulness. METHODOLOGY/PRINCIPAL FINDINGS: We use a transgenic yeast expression system to build on previous studies that described the adaptive landscape for the antifolate drug pyrimethamine, and we describe the most likely evolutionary trajectories for the evolution of drug resistance to the antifolate chlorcycloguanil. We find that the adaptive landscape for chlorcycloguanil is multi-peaked, not all highly resistant alleles are equally accessible by evolution, and there are both commonalities and differences in adaptive landscapes for chlorcycloguanil and pyrimethamine. CONCLUSIONS/SIGNIFICANCE: Our findings suggest that cross-resistance between drugs targeting the same enzyme reflect the fitness landscapes associated with each particular drug and the position of the genotype on both landscapes. The possible public health implications of these findings are discussed.

}, keywords = {*Drug Resistance, *Evolution, Molecular, Folic Acid Antagonists/*pharmacology, Malaria, Falciparum/*drug therapy/enzymology/parasitology, Plasmodium falciparum/*drug effects/enzymology, Proguanil/pharmacology, Pyrimethamine/pharmacology, Tetrahydrofolate Dehydrogenase/chemistry/*metabolism, Triazines/pharmacology}, isbn = {1932-6203 (Electronic)1932-6203 (Linking)}, author = {Costanzo, M. S. and Brown, K. M. and Hartl, D. L.} } @article {540101, title = {Identification and functional validation of the novel antimalarial resistance locus PF10_0355 in Plasmodium falciparum}, journal = {PLoS Genet}, volume = {7}, number = {4}, year = {2011}, note = {

Van Tyne, DariaPark, Daniel JSchaffner, Stephen FNeafsey, Daniel EAngelino, ElaineCortese, Joseph FBarnes, Kayla GRosen, David MLukens, Amanda KDaniels, Rachel FMilner, Danny A JrJohnson, Charles AShlyakhter, IlyaGrossman, Sharon RBecker, Justin SYamins, DanielKarlsson, Elinor KNdiaye, DaoudaSarr, OusmaneMboup, SouleymaneHappi, ChristianFurlotte, Nicholas AEskin, EleazarKang, Hyun MinHartl, Daniel LBirren, Bruce WWiegand, Roger CLander, Eric SWirth, Dyann FVolkman, Sarah KSabeti, Pardis CengK25 HL080079/HL/NHLBI NIH HHS/T32 AI007638/AI/NIAID NIH HHS/T32 GM007753/GM/NIGMS NIH HHS/Research Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov{\textquoteright}tResearch Support, U.S. Gov{\textquoteright}t, Non-P.H.S.2011/05/03 06:00PLoS Genet. 2011 Apr;7(4):e1001383. doi: 10.1371/journal.pgen.1001383. Epub 2011 Apr 21.

}, month = {Apr}, pages = {e1001383}, abstract = {

The Plasmodium falciparum parasite{\textquoteright}s ability to adapt to environmental pressures, such as the human immune system and antimalarial drugs, makes malaria an enduring burden to public health. Understanding the genetic basis of these adaptations is critical to intervening successfully against malaria. To that end, we created a high-density genotyping array that assays over 17,000 single nucleotide polymorphisms ( approximately 1 SNP/kb), and applied it to 57 culture-adapted parasites from three continents. We characterized genome-wide genetic diversity within and between populations and identified numerous loci with signals of natural selection, suggesting their role in recent adaptation. In addition, we performed a genome-wide association study (GWAS), searching for loci correlated with resistance to thirteen antimalarials; we detected both known and novel resistance loci, including a new halofantrine resistance locus, PF10_0355. Through functional testing we demonstrated that PF10_0355 overexpression decreases sensitivity to halofantrine, mefloquine, and lumefantrine, but not to structurally unrelated antimalarials, and that increased gene copy number mediates resistance. Our GWAS and follow-on functional validation demonstrate the potential of genome-wide studies to elucidate functionally important loci in the malaria parasite genome.

}, keywords = {*Genetic Loci, Antimalarials/*pharmacology, Drug Resistance/*genetics, Ethanolamines/pharmacology, Fluorenes/pharmacology, Gene Dosage, Gene Expression, Genetic Association Studies, Genetic Variation, Genotype, Haplotypes, Linkage Disequilibrium, Malaria, Falciparum/parasitology/prevention \& control, Mefloquine/pharmacology, Phenanthrenes/pharmacology, Plasmodium falciparum/drug effects/*genetics, Polymorphism, Single Nucleotide, Selection, Genetic}, isbn = {1553-7404 (Electronic)1553-7390 (Linking)}, author = {Van Tyne, D. and Park, D. J. and Schaffner, S. F. and Neafsey, D. E. and Angelino, E. and Cortese, J. F. and Barnes, K. G. and Rosen, D. M. and Lukens, A. K. and Daniels, R. F. and Milner, D. A., Jr. and Johnson, C. A. and Shlyakhter, I. and Grossman, S. R. and Becker, J.S. and Yamins, D. and Karlsson, E. K. and Ndiaye, D. and Sarr, O. and Mboup, S. and Happi, C. and Furlotte, N. A. and Eskin, E. and Kang, H. M. and Hartl, D. L. and Birren, B. W. and Wiegand, R. C. and Lander, E. S. and Wirth, DF and Volkman, S. K. and Sabeti, P. C.} } @article {539976, title = {Interspecific Y chromosome introgressions disrupt testis-specific gene expression and male reproductive phenotypes in Drosophila}, journal = {Proc Natl Acad Sci U S A}, volume = {108}, number = {41}, year = {2011}, note = {

Sackton, Timothy BMontenegro, HoracioHartl, Daniel LLemos, BernardoengF32 GM086950/GM/NIGMS NIH HHS/F32 GM086950-01/GM/NIGMS NIH HHS/F32 GM086950-02/GM/NIGMS NIH HHS/F32 GM086950-03/GM/NIGMS NIH HHS/R01 GM084236/GM/NIGMS NIH HHS/R01 GM084236-03/GM/NIGMS NIH HHS/Research Support, N.I.H., Extramural2011/10/05 06:00Proc Natl Acad Sci U S A. 2011 Oct 11;108(41):17046-51. doi: 10.1073/pnas.1114690108. Epub 2011 Oct 3.

}, month = {Oct 11}, pages = {17046-51}, abstract = {

The Drosophila Y chromosome is a degenerated, heterochromatic chromosome with few functional genes. Nonetheless, natural variation on the Y chromosome in Drosophila melanogaster has substantial trans-acting effects on the regulation of X-linked and autosomal genes. However, the contribution of Y chromosome divergence to gene expression divergence between species is unknown. In this study, we constructed a series of Y chromosome introgression lines, in which Y chromosomes from either Drosophila sechellia or Drosophila simulans are introgressed into a common D. simulans genetic background. Using these lines, we compared genome-wide gene expression and male reproductive phenotypes between heterospecific and conspecific Y chromosomes. We find significant differences in expression for 122 genes, or 2.84\% of all genes analyzed. Genes down-regulated in males with heterospecific Y chromosomes are significantly biased toward testis-specific expression patterns. These same lines show reduced fecundity and sperm competitive ability. Taken together, these results imply a significant role for Y/X and Y/autosome interactions in maintaining proper expression of male-specific genes, either directly or via indirect effects on male reproductive tissue development or function.

}, keywords = {Animals, Animals, Genetically Modified, Biological Evolution, Drosophila melanogaster/genetics/physiology, Drosophila/*genetics/physiology, Gene Expression, Genetic Fitness/*genetics, Male, Metabolism/genetics, Organ Specificity, Phenotype, Species Specificity, Testis/physiology, Y Chromosome/*genetics}, isbn = {1091-6490 (Electronic)0027-8424 (Linking)}, author = {Sackton, T. B. and Montenegro, H. and Hartl, D. L. and Lemos, B.} } @article {539206, title = {James F. Crow and the art of teaching and mentoring}, journal = {Genetics}, volume = {189}, number = {4}, year = {2011}, note = {

Hartl, Daniel LengBiographyHistorical Article2011/12/17 06:00Genetics. 2011 Dec;189(4):1129-33. doi: 10.1534/genetics.111.135160.

}, month = {Dec}, pages = {1129-33}, abstract = {

To honor James F. Crow on the occasion of his 95th birthday, GENETICS has commissioned a series of Perspectives and Reviews. For GENETICS to publish the honorifics is fitting, as from their birth Crow and GENETICS have been paired. Crow was scheduled to be born in January 1916, the same month that the first issue of GENETICS was scheduled to appear, and in the many years that Crow has made major contributions to the conceptual foundations of modern genetics, GENETICS has chronicled his and other major advances in the field. The commissioned Perspectives and Reviews summarize and celebrate Professor Crow{\textquoteright}s contributions as a research scientist, administrator, colleague, community supporter, international leader, teacher, and mentor. In science, Professor Crow was the international leader of his generation in the application of genetics to populations of organisms and in uncovering the role of genetics in health and disease. In education, he was a superb undergraduate teacher whose inspiration changed the career paths of many students. His teaching skills are legendary, his lectures urbane and witty, rigorous and clear. He was also an extraordinary mentor to numerous graduate students and postdoctoral fellows, many of whom went on to establish successful careers of their own. In public service, Professor Crow served in key administrative positions at the University of Wisconsin, participated as a member of numerous national and international committees, and served as president of both the Genetics Society of America and the American Society for Human Genetics. This Perspective examines Professor Crow as teacher and mentor through the eyes and experiences of one student who was enrolled in his genetics course as an undergraduate and who later studied with him as a graduate student.

}, keywords = {*Mentors, *Teaching, Genetics/*education, History, 20th Century, History, 21st Century, United States}, isbn = {1943-2631 (Electronic)0016-6731 (Linking)}, author = {Hartl, D. L.} } @article {539026, title = {Misfolded proteins impose a dosage-dependent fitness cost and trigger a cytosolic unfolded protein response in yeast}, journal = {Proc Natl Acad Sci U S A}, volume = {108}, number = {2}, year = {2011}, note = {

Geiler-Samerotte, Kerry ADion, Michael FBudnik, Bogdan AWang, Stephanie MHartl, Daniel LDrummond, D Allaneng1R01GM088344-01/GM/NIGMS NIH HHS/GM065169/GM/NIGMS NIH HHS/GM079536/GM/NIGMS NIH HHS/P50GM068763/GM/NIGMS NIH HHS/R01 GM088344/GM/NIGMS NIH HHS/Research Support, N.I.H., Extramural2010/12/29 06:00Proc Natl Acad Sci U S A. 2011 Jan 11;108(2):680-5. doi: 10.1073/pnas.1017570108. Epub 2010 Dec 27.

}, month = {Jan 11}, pages = {680-5}, abstract = {

Evolving lineages face a constant intracellular threat: most new coding sequence mutations destabilize the folding of the encoded protein. Misfolded proteins form insoluble aggregates and are hypothesized to be intrinsically cytotoxic. Here, we experimentally isolate a fitness cost caused by toxicity of misfolded proteins. We exclude other costs of protein misfolding, such as loss of functional protein or attenuation of growth-limiting protein synthesis resources, by comparing growth rates of budding yeast expressing folded or misfolded variants of a gratuitous protein, YFP, at equal levels. We quantify a fitness cost that increases with misfolded protein abundance, up to as much as a 3.2\% growth rate reduction when misfolded YFP represents less than 0.1\% of total cellular protein. Comparable experiments on variants of the yeast gene orotidine-5{\textquoteright}-phosphate decarboxylase (URA3) produce similar results. Quantitative proteomic measurements reveal that, within the cell, misfolded YFP induces coordinated synthesis of interacting cytosolic chaperone proteins in the absence of a wider stress response, providing evidence for an evolved modular response to misfolded proteins in the cytosol. These results underscore the distinct and evolutionarily relevant molecular threat of protein misfolding, independent of protein function. Assuming that most misfolded proteins impose similar costs, yeast cells express almost all proteins at steady-state levels sufficient to expose their encoding genes to selection against misfolding, lending credibility to the recent suggestion that such selection imposes a global constraint on molecular evolution.

}, keywords = {Bacterial Proteins/chemistry, Cytosol/*chemistry/metabolism, Evolution, Molecular, Fungal Proteins/*chemistry, Hot Temperature, Luminescent Proteins/chemistry, Molecular Chaperones/chemistry, Protein Denaturation, protein folding, Proteins/chemistry, Proteomics/methods, Saccharomyces cerevisiae Proteins/chemistry, Saccharomyces cerevisiae/metabolism, Transcription, Genetic}, isbn = {1091-6490 (Electronic)0027-8424 (Linking)}, author = {Geiler-Samerotte, K. A. and Dion, M. F. and Budnik, B. A. and Wang, S. M. and Hartl, D. L. and Drummond, D. A.} } @article {538731, title = {Model transcriptional networks with continuously varying expression levels}, journal = {BMC Evol Biol}, volume = {11}, year = {2011}, note = {

Carneiro, Mauricio OTaubes, Clifford HHartl, Daniel LengGM07953/GM/NIGMS NIH HHS/Research Support, N.I.H., ExtramuralEngland2011/12/21 06:00BMC Evol Biol. 2011 Dec 19;11:363. doi: 10.1186/1471-2148-11-363.

}, pages = {363}, abstract = {

BACKGROUND: At a time when genomes are being sequenced by the hundreds, much attention has shifted from identifying genes and phenotypes to understanding the networks of interactions among genes. We developed a gene network developmental model expanding on previous models of transcription regulatory networks. In our model, each network is described by a matrix representing the interactions between transcription factors, and a vector of continuous values representing the transcription factor expression in an individual. RESULTS: In this work we used the gene network model to look at the impact of mating as well as insertions and deletions of genes in the evolution of complexity of these networks. We found that the natural process of diploid mating increases the likelihood of maintaining complexity, especially in higher order networks (more than 10 genes). We also show that gene insertion is a very efficient way to add more genes to a network as it provides a much higher chance of developmental stability. CONCLUSIONS: The continuous model affords a more complete view of the evolution of interacting genes. The notion of a continuous output vector also incorporates the reality of gene networks and graded concentrations of gene products.

}, keywords = {*Evolution, Molecular, *Gene Regulatory Networks, *Models, Genetic, Computer Simulation, Mutagenesis, Insertional, Sequence Deletion}, isbn = {1471-2148 (Electronic)1471-2148 (Linking)}, author = {Carneiro, M. O. and Taubes, C. H. and Hartl, D. L.} } @article {539826, title = {Ribosomal DNA deletions modulate genome-wide gene expression: "rDNA-sensitive" genes and natural variation}, journal = {PLoS Genet}, volume = {7}, number = {4}, year = {2011}, note = {

Paredes, SilvanaBranco, Alan THartl, Daniel LMaggert, Keith ALemos, BernardoengR01 GM076092/GM/NIGMS NIH HHS/R01 GM084236/GM/NIGMS NIH HHS/R01 GM084236-03/GM/NIGMS NIH HHS/Research Support, N.I.H., Extramural2011/05/03 06:00PLoS Genet. 2011 Apr;7(4):e1001376. doi: 10.1371/journal.pgen.1001376. Epub 2011 Apr 21.

}, month = {Apr}, pages = {e1001376}, abstract = {

The ribosomal rDNA gene array is an epigenetically-regulated repeated gene locus. While rDNA copy number varies widely between and within species, the functional consequences of subtle copy number polymorphisms have been largely unknown. Deletions in the Drosophila Y-linked rDNA modifies heterochromatin-induced position effect variegation (PEV), but it has been unknown if the euchromatic component of the genome is affected by rDNA copy number. Polymorphisms of naturally occurring Y chromosomes affect both euchromatin and heterochromatin, although the elements responsible for these effects are unknown. Here we show that copy number of the Y-linked rDNA array is a source of genome-wide variation in gene expression. Induced deletions in the rDNA affect the expression of hundreds to thousands of euchromatic genes throughout the genome of males and females. Although the affected genes are not physically clustered, we observed functional enrichments for genes whose protein products are located in the mitochondria and are involved in electron transport. The affected genes significantly overlap with genes affected by natural polymorphisms on Y chromosomes, suggesting that polymorphic rDNA copy number is an important determinant of gene expression diversity in natural populations. Altogether, our results indicate that subtle changes to rDNA copy number between individuals may contribute to biologically relevant phenotypic variation.

}, keywords = {*Gene Deletion, Animals, Cell Nucleus/genetics, Crosses, Genetic, DNA Copy Number Variations, DNA, Ribosomal/*genetics, Drosophila/*genetics, Euchromatin/*genetics, Female, Gene Expression, Genetic Loci, Male, Oligonucleotide Array Sequence Analysis, Polymorphism, Genetic, Y Chromosome/genetics}, isbn = {1553-7404 (Electronic)1553-7390 (Linking)}, author = {Paredes, S. and Branco, A. T. and Hartl, D. L. and Maggert, K. A. and Lemos, B.} } @article {539936, title = {Adaptive impact of the chimeric gene Quetzalcoatl in Drosophila melanogaster}, journal = {Proc Natl Acad Sci U S A}, volume = {107}, number = {24}, year = {2010}, note = {

Rogers, Rebekah LBedford, TrevorLyons, Ana MHartl, Daniel LengGM065169/GM/NIGMS NIH HHS/GM084236/GM/NIGMS NIH HHS/Research Support, N.I.H., Extramural2010/06/11 06:00Proc Natl Acad Sci U S A. 2010 Jun 15;107(24):10943-8. doi: 10.1073/pnas.1006503107. Epub 2010 Jun 1.

}, month = {Jun 15}, pages = {10943-8}, abstract = {

Chimeric genes, which form through the genomic fusion of two protein-coding genes, are a significant source of evolutionary novelty in Drosophila melanogaster. However, the propensity of chimeric genes to produce adaptive phenotypic changes is not fully understood. Here, we describe the chimeric gene Quetzalcoatl (Qtzl; CG31864), which formed in the recent past and swept to fixation in D. melanogaster. Qtzl arose through a duplication on chromosome 2L that united a portion of the mitochondrially targeted peptide CG12264 with a segment of the polycomb gene escl. The 3{\textquoteright} segment of the gene, which is derived from escl, is inherited out of frame, producing a unique peptide sequence. Nucleotide diversity is drastically reduced and site frequency spectra are significantly skewed surrounding the duplicated region, a finding consistent with a selective sweep on the duplicate region containing Qtzl. Qtzl has an expression profile that largely resembles that of escl, with expression in early pupae, adult females, and male testes. However, expression patterns appear to have been decoupled from both parental genes during later embryonic development and in head tissues of adult males, indicating that Qtzl has developed a distinct regulatory profile through the rearrangement of different 5{\textquoteright} and 3{\textquoteright} regulatory domains. Furthermore, misexpression of Qtzl suppresses defects in the formation of the neuromuscular junction in larvae, demonstrating that Qtzl can produce phenotypic effects in cells. Together, these results show that chimeric genes can produce structural and regulatory changes in a single mutational step and may be a major factor in adaptive evolution.

}, keywords = {*Evolution, Molecular, *Genes, Insect, Adaptation, Physiological/genetics, Animals, Base Sequence, Chimera/genetics, DNA Primers/genetics, Drosophila melanogaster/*genetics/growth \& development/physiology, Drosophila Proteins/genetics, Female, Frameshift Mutation, Gene Duplication, Gene Expression Regulation, Developmental, Gene Fusion, Male, Mutant Chimeric Proteins/genetics, Phenotype, Repressor Proteins/genetics}, isbn = {1091-6490 (Electronic)0027-8424 (Linking)}, author = {Rogers, R. L. and Bedford, T. and Lyons, A. M. and Hartl, D. L.} } @article {539031, title = {Climate change and the integrity of science}, journal = {Science}, volume = {328}, number = {5979}, year = {2010}, note = {

Gleick, P HAdams, R MAmasino, R MAnders, EAnderson, D JAnderson, W WAnselin, L EArroyo, M KAsfaw, BAyala, F JBax, ABebbington, A JBell, GBennett, M V LBennetzen, J LBerenbaum, M RBerlin, O BBjorkman, P JBlackburn, EBlamont, J EBotchan, M RBoyer, J SBoyle, E ABranton, DBriggs, S PBriggs, W RBrill, W JBritten, R JBroecker, W SBrown, J HBrown, P OBrunger, A TCairns, J JrCanfield, D ECarpenter, S RCarrington, J CCashmore, A RCastilla, J CCazenave, AChapin, F S 3rdCiechanover, A JClapham, D EClark, W CClayton, R NCoe, M DConwell, E MCowling, E BCowling, R MCox, C SCroteau, R BCrothers, D MCrutzen, P JDaily, G CDalrymple, G BDangl, J LDarst, S ADavies, D RDavis, M BDe Camilli, P VDean, CDeFries, R SDeisenhofer, JDelmer, D PDeLong, E FDeRosier, D JDiener, T ODirzo, RDixon, J EDonoghue, M JDoolittle, R FDunne, TEhrlich, P REisenstadt, S NEisner, TEmanuel, K AEnglander, S WErnst, W GFalkowski, P GFeher, GFerejohn, J AFersht, AFischer, E HFischer, RFlannery, K VFrank, JFrey, P AFridovich, IFrieden, CFutuyma, D JGardner, W RGarrett, C J RGilbert, WGoldberg, R BGoodenough, W HGoodman, C SGoodman, MGreengard, PHake, SHammel, GHanson, SHarrison, S CHart, S RHartl, D LHaselkorn, RHawkes, KHayes, J MHille, BHokfelt, THouse, J SHout, MHunten, D MIzquierdo, I AJagendorf, A TJanzen, D HJeanloz, RJencks, C SJury, W AKaback, H RKailath, TKay, PKay, S AKennedy, DKerr, AKessler, R CKhush, G SKieffer, S WKirch, P VKirk, KKivelson, M GKlinman, J PKlug, AKnopoff, LKornberg, HKutzbach, J ELagarias, J CLambeck, KLandy, ALangmuir, C HLarkins, B ALe Pichon, X TLenski, R ELeopold, E BLevin, S ALevitt, MLikens, G ELippincott-Schwartz, JLorand, LLovejoy, C OLynch, MMabogunje, A LMalone, T FManabe, SMarcus, JMassey, D SMcWilliams, J CMedina, EMelosh, H JMeltzer, D JMichener, C DMiles, E LMooney, H AMoore, P BMorel, F M MMosley-Thompson, E SMoss, BMunk, W HMyers, NNair, G BNathans, JNester, E WNicoll, R ANovick, R PO{\textquoteright}Connell, J FOlsen, P EOpdyke, N DOster, G FOstrom, EPace, N RPaine, R TPalmiter, R DPedlosky, JPetsko, G APettengill, G HPhilander, S GPiperno, D RPollard, T DPrice, P B JrReichard, P AReskin, B FRicklefs, R ERivest, R LRoberts, J DRomney, A KRossmann, M GRussell, D WRutter, W JSabloff, J ASagdeev, R ZSahlins, M DSalmond, ASanes, J RSchekman, RSchellnhuber, JSchindler, D WSchmitt, JSchneider, S HSchramm, V LSederoff, R RShatz, C JSherman, FSidman, R LSieh, KSimons, E LSinger, B HSinger, M FSkyrms, BSleep, N HSmith, B DSnyder, S HSokal, R RSpencer, C SSteitz, T AStrier, K BSudhof, T CTaylor, S STerborgh, JThomas, D HThompson, L GTjian, R TTurner, M GUyeda, SValentine, J WValentine, J SVan Etten, J Lvan Holde, K EVaughan, MVerba, Svon Hippel, P HWake, D BWalker, AWalker, J EWatson, E BWatson, P JWeigel, DWessler, S RWest-Eberhard, M JWhite, T DWilson, W JWolfenden, R VWood, J AWoodwell, G MWright, H E JrWu, CWunsch, CZoback, M LengHoward Hughes Medical Institute/LetterResearch Support, Non-U.S. Gov{\textquoteright}tNew York, N.Y.2010/05/08 06:00Science. 2010 May 7;328(5979):689-90. doi: 10.1126/science.328.5979.689.

}, month = {May 7}, pages = {689-90}, keywords = {*Climate Change, Politics, Public Policy, Research Personnel, Research/standards}, isbn = {1095-9203 (Electronic)0036-8075 (Linking)}, author = {Gleick, P. H. and Adams, R. M. and Amasino, R. M. and Anders, E. and Anderson, D. J. and Anderson, W. W. and Anselin, L. E. and Arroyo, M. K. and Asfaw, B. and Ayala, F. J. and Bax, A. and Bebbington, A. J. and Bell, G. and Bennett, M. V. and Bennetzen, J. L. and Berenbaum, M. R. and Berlin, O. B. and Bjorkman, P. J. and Blackburn, E. and Blamont, J. E. and Botchan, M. R. and Boyer, J. S. and Boyle, E. A. and Branton, D. and Briggs, S. P. and Briggs, W. R. and Brill, W. J. and Britten, R. J. and Broecker, W. S. and Brown, J. H. and Brown, P. O. and Brunger, A. T. and Cairns, J., Jr. and Canfield, D. E. and Carpenter, S. R. and Carrington, J. C. and Cashmore, A. R. and Castilla, J. C. and Cazenave, A. and Chapin, F. S., 3rd and Ciechanover, A. J. and Clapham, D. E. and Clark, W. C. and Clayton, R. N. and Coe, M. D. and Conwell, E. M. and Cowling, E. B. and Cowling, R. M. and Cox, C. S. and Croteau, R. B. and Crothers, D. M. and Crutzen, P. J. and Daily, G. C. and Dalrymple, G. B. and Dangl, J. L. and Darst, S. A. and Davies, D. R. and Davis, M. B. and De Camilli, P. V. and Dean, C. and DeFries, R. S. and Deisenhofer, J. and Delmer, D. P. and Delong, E. F. and DeRosier, D. J. and Diener, T. O. and Dirzo, R. and Dixon, J. E. and Donoghue, M. J. and Doolittle, R. F. and Dunne, T. and Ehrlich, P. R. and Eisenstadt, S. N. and Eisner, T. and Emanuel, K. A. and Englander, S. W. and Ernst, W. G. and Falkowski, P. G. and Feher, G. and Ferejohn, J. A. and Fersht, A. and Fischer, E. H. and Fischer, R. and Flannery, K. V. and Frank, J. and Frey, P. A. and Fridovich, I. and Frieden, C. and Futuyma, D. J. and Gardner, W. R. and Garrett, C. J. and Gilbert, W. and Goldberg, R. B. and Goodenough, W. H. and Goodman, C. S. and Goodman, M. and Greengard, P. and Hake, S. and Hammel, G. and Hanson, S. and Harrison, S. C. and Hart, S. R. and Hartl, D. L. and Haselkorn, R. and Hawkes, K. and Hayes, J. M. and Hille, B. and Hokfelt, T. and House, J. S. and Hout, M. and Hunten, D. M. and Izquierdo, I. A. and Jagendorf, A. T. and Janzen, D. H. and Jeanloz, R. and Jencks, C. S. and Jury, W. A. and Kaback, H. R. and Kailath, T. and Kay, P. and Kay, S. A. and Kennedy, D. and Kerr, A. and Kessler, R. C. and Khush, G. S. and Kieffer, S. W. and Kirch, P. V. and Kirk, K. and Kivelson, M. G. and Klinman, J. P. and Klug, A. and Knopoff, L. and Kornberg, H. and Kutzbach, J. E. and Lagarias, J. C. and Lambeck, K. and Landy, A. and Langmuir, C. H. and Larkins, B. A. and Le Pichon, X. T. and Lenski, R. E. and Leopold, E. B. and Levin, S. A. and Levitt, M. and Likens, G. E. and Lippincott-Schwartz, J. and Lorand, L. and Lovejoy, C. O. and Lynch, M. and Mabogunje, A. L. and Malone, T. F. and Manabe, S. and Marcus, J. and Massey, D. S. and McWilliams, J. C. and Medina, E. and Melosh, H. J. and Meltzer, D. J. and Michener, C. D. and Miles, E. L. and Mooney, H. A. and Moore, P. B. and Morel, F. M. and Mosley-Thompson, E. S. and Moss, B. and Munk, W. H. and Myers, N. and Nair, G. B. and Nathans, J. and Nester, E. W. and Nicoll, R. A. and Novick, R. P. and O{\textquoteright}Connell, J. F. and Olsen, P. E. and Opdyke, N. D. and Oster, G. F. and Ostrom, E. and Pace, N. R. and Paine, R. T. and Palmiter, R. D. and Pedlosky, J. and Petsko, G. A. and Pettengill, G. H. and Philander, S. G. and Piperno, D. R. and Pollard, T. D. and Price, P. B., Jr. and Reichard, P. A. and Reskin, B. F. and Ricklefs, R. E. and Rivest, R. L. and Roberts, J. D. and Romney, A. K. and Rossmann, M. G. and Russell, D. W. and Rutter, W. J. and Sabloff, J. A. and Sagdeev, R. Z. and Sahlins, M. D. and Salmond, A. and Sanes, J. R. and Schekman, R. and Schellnhuber, J. and Schindler, D. W. and Schmitt, J. and Schneider, S. H. and Schramm, V. L. and Sederoff, R. R. and Shatz, C. J. and Sherman, F. and Sidman, R. L. and Sieh, K. and Simons, E. L. and Singer, B. H. and Singer, M. F. and Skyrms, B. and Sleep, N. H. and Smith, B. D. and Snyder, S. H. and Sokal, R. R. and Spencer, C. S. and Steitz, T. A. and Strier, K. B. and Sudhof, T. C. and Taylor, S. S. and Terborgh, J. and Thomas, D. H. and Thompson, L. G. and Tjian, R. T. and Turner, M. G. and Uyeda, S. and Valentine, J. W. and Valentine, J. S. and Van Etten, J. L. and van Holde, K. E. and Vaughan, M. and Verba, S. and von Hippel, P. H. and Wake, D.B. and Walker, A. and Walker, J. E. and Watson, E. B. and Watson, P. J. and Weigel, D. and Wessler, S. R. and West-Eberhard, M. J. and White, T. D. and Wilson, W. J. and Wolfenden, R. V. and Wood, J. A. and Woodwell, G. M. and Wright, H. E., Jr. and Wu, C. and Wunsch, C. and Zoback, M. L.} } @article {538726, title = {Colloquium papers: Adaptive landscapes and protein evolution}, journal = {Proc Natl Acad Sci U S A}, volume = {107 Suppl 1}, year = {2010}, note = {

Carneiro, MauricioHartl, Daniel LengR01GM079536/GM/NIGMS NIH HHS/Research Support, N.I.H., ExtramuralReview2009/10/07 06:00Proc Natl Acad Sci U S A. 2010 Jan 26;107 Suppl 1:1747-51. doi: 10.1073/pnas.0906192106. Epub 2009 Sep 30.

}, month = {Jan 26}, pages = {1747-51}, abstract = {

The principles governing protein evolution under strong selection are important because of the recent history of evolved resistance to insecticides, antibiotics, and vaccines. One experimental approach focuses on studies of mutant proteins and all combinations of mutant sites that could possibly be intermediates in the evolutionary pathway to resistance. In organisms carrying each of the engineered proteins, a measure of protein function or a proxy for fitness is estimated. The correspondence between protein sequence and fitness is widely known as a fitness landscape or adaptive landscape. Here, we examine some empirical fitness landscapes and compare them with simulated landscapes in which the fitnesses are randomly assigned. We find that mutant sites in real proteins show significantly more additivity than those obtained from random simulations. The high degree of additivity is reflected in a summary statistic for adaptive landscapes known as the "roughness," which for the actual proteins so far examined lies in the smallest 0.5\% tail of random landscapes.

}, keywords = {*Evolution, Molecular, Computer Simulation, Mutation, Proteins/chemistry/*genetics}, isbn = {1091-6490 (Electronic)0027-8424 (Linking)}, author = {Carneiro, M. and Hartl, D. L.} } @article {538651, title = {Compensatory mutations restore fitness during the evolution of dihydrofolate reductase}, journal = {Mol Biol Evol}, volume = {27}, number = {12}, year = {2010}, note = {

Brown, Kyle MCostanzo, Marna SXu, WenxinRoy, ScottLozovsky, Elena RHartl, Daniel LengR01GM079536/GM/NIGMS NIH HHS/Research Support, N.I.H., ExtramuralResearch Support, U.S. Gov{\textquoteright}t, Non-P.H.S.2010/06/26 06:00Mol Biol Evol. 2010 Dec;27(12):2682-90. doi: 10.1093/molbev/msq160. Epub 2010 Jun 24.

}, month = {Dec}, pages = {2682-90}, abstract = {

Whether a trade-off exists between robustness and evolvability is an important issue for protein evolution. Although traditional viewpoints have assumed that existing functions must be compromised by the evolution of novel activities, recent research has suggested that existing phenotypes can be robust to the evolution of novel protein functions. Enzymes that are targets of antibiotics that are competitive inhibitors must evolve decreased drug affinity while maintaining their function and sustaining growth. Utilizing a transgenic Saccharomyces cerevisiae model expressing the dihydrofolate reductase (DHFR) enzyme from the malarial parasite Plasmodium falciparum, we examine the robustness of growth rate to drug-resistance mutations. We assay the growth rate and resistance of all 48 combinations of 6 DHFR point mutations associated with increased drug resistance in field isolates of the parasite. We observe no consistent relationship between growth rate and resistance phenotypes among the DHFR alleles. The three evolutionary pathways that dominate DHFR evolution show that mutations with increased resistance can compensate for initial declines in growth rate from previously acquired mutations. In other words, resistance mutations that occur later in evolutionary trajectories can compensate for the fitness consequences of earlier mutations. Our results suggest that high levels of resistance may be selected for without necessarily jeopardizing overall fitness.

}, keywords = {*Evolution, Molecular, *Genetic Fitness, Alleles, Antimalarials/*pharmacology, Drug Resistance, Genes, Protozoan, Models, Genetic, Phenotype, Plasmodium falciparum/enzymology/*genetics, Point Mutation, Pyrimethamine/*pharmacology, Saccharomyces cerevisiae/enzymology/genetics, Tetrahydrofolate Dehydrogenase/*genetics/metabolism}, isbn = {1537-1719 (Electronic)0737-4038 (Linking)}, author = {Brown, K. M. and Costanzo, M. S. and Xu, W. and Roy, S. and Lozovsky, E. R. and Hartl, D. L.} } @article {539546, title = {Epigenetic effects of polymorphic Y chromosomes modulate chromatin components, immune response, and sexual conflict}, journal = {Proc Natl Acad Sci U S A}, volume = {107}, number = {36}, year = {2010}, note = {

Lemos, BernardoBranco, Alan THartl, Daniel LengGM084236/GM/NIGMS NIH HHS/Research Support, N.I.H., Extramural2010/08/28 06:00Proc Natl Acad Sci U S A. 2010 Sep 7;107(36):15826-31. doi: 10.1073/pnas.1010383107. Epub 2010 Aug 23.

}, month = {Sep 7}, pages = {15826-31}, abstract = {

Genetic conflicts between sexes and generations provide a foundation for understanding the functional evolution of sex chromosomes and sexually dimorphic phenotypes. Y chromosomes of Drosophila contain multi-megabase stretches of satellite DNA repeats and a handful of protein-coding genes that are monomorphic within species. Nevertheless, polymorphic variation in heterochromatic Y chromosomes of Drosophila result in genome-wide gene expression variation. Here we show that such naturally occurring Y-linked regulatory variation (YRV) can be detected in somatic tissues and contributes to the epigenetic balance of heterochromatin/euchromatin at three distinct loci showing position-effect variegation (PEV). Moreover, polymorphic Y chromosomes differentially affect the expression of thousands of genes in XXY female genotypes in which Y-linked protein-coding genes are not transcribed. The data show a disproportionate influence of YRV on the variable expression of genes whose protein products localize to the nucleus, have nucleic-acid binding activity, and are involved in transcription, chromosome organization, and chromatin assembly. These include key components such as HP1, Trithorax-like (GAGA factor), Su(var)3-9, Brahma, MCM2, ORC2, and inner centromere protein. Furthermore, mitochondria-related genes, immune response genes, and transposable elements are also disproportionally affected by Y chromosome polymorphism. These functional clusterings may arise as a consequence of the involvement of Y-linked heterochromatin in the origin and resolution of genetic conflicts between males and females. Taken together, our results indicate that Y chromosome heterochromatin serves as a major source of epigenetic variation in natural populations that interacts with chromatin components to modulate the expression of biologically relevant phenotypic variation.

}, keywords = {*Epigenesis, Genetic, *Polymorphism, Genetic, *Sexual Behavior, Animal, *Y Chromosome, Animals, Chromatin/*physiology, Drosophila/genetics/immunology/*physiology, Female}, isbn = {1091-6490 (Electronic)0027-8424 (Linking)}, author = {Lemos, B. and Branco, A. T. and Hartl, D. L.} } @article {538511, title = {Fine-scale genetic mapping of a hybrid sterility factor between Drosophila simulans and D. mauritiana: the varied and elusive functions of "speciation genes"}, journal = {BMC Evol Biol}, volume = {10}, year = {2010}, note = {

Araripe, Luciana OMontenegro, HoracioLemos, BernardoHartl, Daniel LengGM065169/GM/NIGMS NIH HHS/Research Support, N.I.H., ExtramuralEngland2010/12/15 06:00BMC Evol Biol. 2010 Dec 14;10:385. doi: 10.1186/1471-2148-10-385.

}, pages = {385}, abstract = {

BACKGROUND: Hybrid male sterility (HMS) is a usual outcome of hybridization between closely related animal species. It arises because interactions between alleles that are functional within one species may be disrupted in hybrids. The identification of genes leading to hybrid sterility is of great interest for understanding the evolutionary process of speciation. In the current work we used marked P-element insertions as dominant markers to efficiently locate one genetic factor causing a severe reduction in fertility in hybrid males of Drosophila simulans and D. mauritiana. RESULTS: Our mapping effort identified a region of 9 kb on chromosome 3, containing three complete and one partial coding sequences. Within this region, two annotated genes are suggested as candidates for the HMS factor, based on the comparative molecular characterization and public-source information. Gene Taf1 is partially contained in the region, but yet shows high polymorphism with four fixed non-synonymous substitutions between the two species. Its molecular functions involve sequence-specific DNA binding and transcription factor activity. Gene agt is a small, intronless gene, whose molecular function is annotated as methylated-DNA-protein-cysteine S-methyltransferase activity. High polymorphism and one fixed non-synonymous substitution suggest this is a fast evolving gene. The gene trees of both genes perfectly separate D. simulans and D. mauritiana into monophyletic groups. Analysis of gene expression using microarray revealed trends that were similar to those previously found in comparisons between whole-genome hybrids and parental species. CONCLUSIONS: The identification following confirmation of the HMS candidate gene will add another case study leading to understanding the evolutionary process of hybrid incompatibility.

}, keywords = {*Chromosome Mapping, *Genetic Speciation, *Hybridization, Genetic, Animals, Drosophila/*genetics, Epistasis, Genetic, Evolution, Molecular, Female, Gene Expression Profiling, Genes, Insect, Genotype, Infertility, Male/*genetics, Male, Oligonucleotide Array Sequence Analysis, Phylogeny, Polymorphism, Genetic, Sequence Analysis, DNA}, isbn = {1471-2148 (Electronic)1471-2148 (Linking)}, author = {Araripe, L. O. and Montenegro, H. and Lemos, B. and Hartl, D. L.} } @article {539051, title = {Geographic structure of Plasmodium vivax: microsatellite analysis of parasite populations from Sri Lanka, Myanmar, and Ethiopia}, journal = {Am J Trop Med Hyg}, volume = {82}, number = {2}, year = {2010}, note = {

Gunawardena, SharminiKarunaweera, Nadira DFerreira, Marcelo UPhone-Kyaw, MyattPollack, Richard JAlifrangis, MichaelRajakaruna, Rupika SKonradsen, FlemmingAmerasinghe, Priyanie HSchousboe, Mette LGalappaththy, Gawrie N LAbeyasinghe, Rabindra RHartl, Daniel LWirth, Dyann Feng5R03 TW 007966-02/TW/FIC NIH HHS/Research Support, N.I.H., Extramural2010/02/06 06:00Am J Trop Med Hyg. 2010 Feb;82(2):235-42. doi: 10.4269/ajtmh.2010.09-0588.

}, month = {Feb}, pages = {235-42}, abstract = {

Genetic diversity and population structure of Plasmodium vivax parasites can predict the origin and spread of novel variants within a population enabling population specific malaria control measures. We analyzed the genetic diversity and population structure of 425 P. vivax isolates from Sri Lanka, Myanmar, and Ethiopia using 12 trinucleotide and tetranucleotide microsatellite markers. All three parasite populations were highly polymorphic with 3-44 alleles per locus. Approximately 65\% were multiple-clone infections. Mean genetic diversity (H(E)) was 0.7517 in Ethiopia, 0.8450 in Myanmar, and 0.8610 in Sri Lanka. Significant linkage disequilibrium was maintained. Population structure showed two clusters (Asian and African) according to geography and ancestry. Strong clustering of outbreak isolates from Sri Lanka and Ethiopia was observed. Predictive power of ancestry using two-thirds of the isolates as a model identified 78.2\% of isolates accurately as being African or Asian. Microsatellite analysis is a useful tool for mapping short-term outbreaks of malaria and for predicting ancestry.

}, keywords = {*Genetic Variation, demography, Ethiopia, Humans, Linkage Disequilibrium, Microsatellite Repeats, Myanmar, Plasmodium vivax/*genetics, Sri Lanka}, isbn = {1476-1645 (Electronic)0002-9637 (Linking)}, author = {Gunawardena, S. and Karunaweera, N. D. and Ferreira, M. U. and Phone-Kyaw, M. and Pollack, R. J. and Alifrangis, M. and Rajakaruna, R. S. and Konradsen, F. and Amerasinghe, P. H. and Schousboe, M. L. and Galappaththy, G. N. and Abeyasinghe, R. R. and Hartl, D. L. and Wirth, DF} } @article {538996, title = {Key considerations for measuring allelic expression on a genomic scale using high-throughput sequencing}, journal = {Mol Ecol}, volume = {19 Suppl 1}, year = {2010}, note = {

Fontanillas, PierreLandry, Christian RWittkopp, Patricia JRuss, CarstenGruber, Jonathan DNusbaum, ChadHartl, Daniel LengGM065169/GM/NIGMS NIH HHS/GM068465/GM/NIGMS NIH HHS/R01 GM084236/GM/NIGMS NIH HHS/R01 GM084236-03/GM/NIGMS NIH HHS/Research Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov{\textquoteright}tResearch Support, U.S. Gov{\textquoteright}t, Non-P.H.S.England2010/04/02 06:00Mol Ecol. 2010 Mar;19 Suppl 1:212-27. doi: 10.1111/j.1365-294X.2010.04472.x.

}, month = {Mar}, pages = {212-27}, abstract = {

Differences in gene expression are thought to be an important source of phenotypic diversity, so dissecting the genetic components of natural variation in gene expression is important for understanding the evolutionary mechanisms that lead to adaptation. Gene expression is a complex trait that, in diploid organisms, results from transcription of both maternal and paternal alleles. Directly measuring allelic expression rather than total gene expression offers greater insight into regulatory variation. The recent emergence of high-throughput sequencing offers an unprecedented opportunity to study allelic transcription at a genomic scale for virtually any species. By sequencing transcript pools derived from heterozygous individuals, estimates of allelic expression can be directly obtained. The statistical power of this approach is influenced by the number of transcripts sequenced and the ability to unambiguously assign individual sequence fragments to specific alleles on the basis of transcribed nucleotide polymorphisms. Here, using mathematical modelling and computer simulations, we determine the minimum sequencing depth required to accurately measure relative allelic expression and detect allelic imbalance via high-throughput sequencing under a variety of conditions. We conclude that, within a species, a minimum of 500-1000 sequencing reads per gene are needed to test for allelic imbalance, and consequently, at least five to 10 millions reads are required for studying a genome expressing 10 000 genes. Finally, using 454 sequencing, we illustrate an application of allelic expression by testing for cis-regulatory divergence between closely related Drosophila species.

}, keywords = {*Alleles, *Models, Statistical, Animals, Computer Simulation, Drosophila/genetics, Gene Expression, Gene Library, Genomics/*methods, Polymorphism, Single Nucleotide, Sequence Analysis, DNA/*methods}, isbn = {1365-294X (Electronic)0962-1083 (Linking)}, author = {Fontanillas, P. and Landry, C. R. and Wittkopp, P. J. and Russ, C. and Gruber, J. D. and Nusbaum, C. and Hartl, D. L.} } @article {540186, title = {Low-complexity regions in Plasmodium falciparum: missing links in the evolution of an extreme genome}, journal = {Mol Biol Evol}, volume = {27}, number = {9}, year = {2010}, note = {

Zilversmit, Martine MVolkman, Sarah KDePristo, Mark AWirth, Dyann FAwadalla, PhilipHartl, Daniel LengGM079536/GM/NIGMS NIH HHS/GM61351/GM/NIGMS NIH HHS/Research Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov{\textquoteright}t2010/04/30 06:00Mol Biol Evol. 2010 Sep;27(9):2198-209. doi: 10.1093/molbev/msq108. Epub 2010 Apr 28.

}, month = {Sep}, pages = {2198-209}, abstract = {

Over the past decade, attempts to explain the unusual size and prevalence of low-complexity regions (LCRs) in the proteins of the human malaria parasite Plasmodium falciparum have used both neutral and adaptive models. This past research has offered conflicting explanations for LCR characteristics and their role in, and influence on, the evolution of genome structure. Here we show that P. falciparum LCRs (PfLCRs) are not a single phenomenon, but rather consist of at least three distinct types of sequence, and this heterogeneity is the source of the conflict in the literature. Using molecular and population genetics, we show that these families of PfLCRs are evolving by different mechanisms. One of these families, named here the HighGC family, is of particular interest because these LCRs act as recombination hotspots, both in genes under positive selection for high levels of diversity which can be created by recombination (antigens) and those likely to be evolving neutrally or under negative selection (metabolic enzymes). We discuss how the discovery of these distinct species of PfLCRs helps to resolve previous contradictory studies on LCRs in malaria and contributes to our understanding of the evolution of the of the parasite{\textquoteright}s unusual genome.

}, keywords = {*Evolution, Molecular, Animals, Genome, Protozoan/*genetics, Plasmodium falciparum/*genetics}, isbn = {1537-1719 (Electronic)0737-4038 (Linking)}, author = {Zilversmit, M. M. and Volkman, S. K. and Depristo, M. A. and Wirth, DF and Awadalla, P. and Hartl, D. L.} } @article {539441, title = {Recurrent selection on the Winters sex-ratio genes in Drosophila simulans}, journal = {Genetics}, volume = {184}, number = {1}, year = {2010}, note = {

Kingan, Sarah BGarrigan, DanielHartl, Daniel LengGM065169/GM/NIGMS NIH HHS/Research Support, N.I.H., Extramural2009/11/10 06:00Genetics. 2010 Jan;184(1):253-65. doi: 10.1534/genetics.109.109587. Epub 2009 Nov 6.

}, month = {Jan}, pages = {253-65}, abstract = {

Selfish genes, such as meiotic drive elements, propagate themselves through a population without increasing the fitness of host organisms. X-linked (or Y-linked) meiotic drive elements reduce the transmission of the Y (X) chromosome and skew progeny and population sex ratios, leading to intense conflict among genomic compartments. Drosophila simulans is unusual in having a least three distinct systems of X chromosome meiotic drive. Here, we characterize naturally occurring genetic variation at the Winters sex-ratio driver (Distorter on the X or Dox), its progenitor gene (Mother of Dox or MDox), and its suppressor gene (Not Much Yang or Nmy), which have been previously mapped and characterized. We survey three North American populations as well as 13 globally distributed strains and present molecular polymorphism data at the three loci. We find that all three genes show signatures of selection in North America, judging from levels of polymorphism and skews in the site-frequency spectrum. These signatures likely result from the biased transmission of the driver and selection on the suppressor for the maintenance of equal sex ratios. Coalescent modeling indicates that the timing of selection is more recent than the age of the alleles, suggesting that the driver and suppressor are coevolving under an evolutionary "arms race." None of the Winters sex-ratio genes are fixed in D. simulans, and at all loci we find ancestral alleles, which lack the gene insertions and exhibit high levels of nucleotide polymorphism compared to the derived alleles. In addition, we find several "null" alleles that have mutations on the derived Dox background, which result in loss of drive function. We discuss the possible causes of the maintenance of presence-absence polymorphism in the Winters sex-ratio genes.

}, keywords = {*Selection, Genetic, *Sex Ratio, Aging/genetics, Alleles, Animals, california, Drosophila/*genetics, Evolution, Molecular, Female, Gene Conversion, Genes, Insect/*genetics, Genetic Loci/genetics, Haplotypes, INDEL Mutation, Linkage Disequilibrium, Male, Nucleotides/genetics, Polymorphism, Genetic, Time Factors, X Chromosome/genetics}, isbn = {1943-2631 (Electronic)0016-6731 (Linking)}, author = {Kingan, SB and D Garrigan and Hartl, D. L.} } @article {539421, title = {Y not a dead end: epistatic interactions between Y-linked regulatory polymorphisms and genetic background affect global gene expression in Drosophila melanogaster}, journal = {Genetics}, volume = {186}, number = {1}, year = {2010}, note = {

Jiang, Pan-PanHartl, Daniel LLemos, BernardoengGM084236/GM/NIGMS NIH HHS/Research Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov{\textquoteright}t2010/06/17 06:00Genetics. 2010 Sep;186(1):109-18. doi: 10.1534/genetics.110.118109. Epub 2010 Jun 15.

}, month = {Sep}, pages = {109-18}, abstract = {

The Y chromosome, inherited without meiotic recombination from father to son, carries relatively few genes in most species. This is consistent with predictions from evolutionary theory that nonrecombining chromosomes lack variation and degenerate rapidly. However, recent work has suggested a dynamic role for the Y chromosome in gene regulation, a finding with important implications for spermatogenesis and male fitness. We studied Y chromosomes from two populations of Drosophila melanogaster that had previously been shown to have major effects on the thermal tolerance of spermatogenesis. We show that these Y chromosomes differentially modify the expression of hundreds of autosomal and X-linked genes. Genes showing Y-linked regulatory variation (YRV) also show an association with immune response and pheromone detection. Indeed, genes located proximal to the euchromatin-heterochromatin boundary of the X chromosome appear particularly responsive to Y-linked variation, including a substantial number of odorant-binding genes. Furthermore, the data show significant regulatory interactions between the Y chromosome and the genetic background of autosomes and X chromosome. Altogether, our findings support the view that interpopulation, Y-linked regulatory polymorphisms can differentially modulate the expression of many genes important to male fitness, and they also point to complex interactions between the Y chromosome and genetic background affecting global gene expression.

}, keywords = {*Gene Expression Profiling, Animals, Drosophila melanogaster/*genetics, Epistasis, Genetic/*genetics, Female, Gene Order/genetics, Genomics, Inbreeding, Male, Multigene Family/genetics, Polymorphism, Genetic/*genetics, Tropical Climate, X Chromosome/genetics, Y Chromosome/*genetics}, isbn = {1943-2631 (Electronic)0016-6731 (Linking)}, author = {Jiang, P. P. and Hartl, D. L. and Lemos, B.} } @article {539931, title = {Formation and longevity of chimeric and duplicate genes in Drosophila melanogaster}, journal = {Genetics}, volume = {181}, number = {1}, year = {2009}, note = {

Rogers, Rebekah LBedford, TrevorHartl, Daniel LengGM065169/GM/NIGMS NIH HHS/GM068465/GM/NIGMS NIH HHS/Research Support, N.I.H., ExtramuralResearch Support, U.S. Gov{\textquoteright}t, Non-P.H.S.2008/11/19 09:00Genetics. 2009 Jan;181(1):313-22. doi: 10.1534/genetics.108.091538. Epub 2008 Nov 17.

}, month = {Jan}, pages = {313-22}, abstract = {

Historically, duplicate genes have been regarded as a major source of novel genetic material. However, recent work suggests that chimeric genes formed through the fusion of pieces of different genes may also contribute to the evolution of novel functions. To compare the contribution of chimeric and duplicate genes to genome evolution, we measured their prevalence and persistence within Drosophila melanogaster. We find that approximately 80.4 duplicates form per million years, but most are rapidly eliminated from the genome, leaving only 4.1\% to be preserved by natural selection. Chimeras form at a comparatively modest rate of approximately 11.4 per million years but follow a similar pattern of decay, with ultimately only 1.4\% of chimeras preserved. We propose two mechanisms of chimeric gene formation, which rely entirely on local, DNA-based mutations to explain the structure and placement of the youngest chimeric genes observed. One involves imprecise excision of an unpaired duplication during large-loop mismatch repair, while the other invokes a process akin to replication slippage to form a chimeric gene in a single event. Our results paint a dynamic picture of both chimeras and duplicate genes within the genome and suggest that chimeric genes contribute substantially to genomic novelty.

}, keywords = {*Evolution, Molecular, Animals, DNA Mismatch Repair/genetics, DNA Replication/genetics, Drosophila melanogaster/*genetics, Genes, Duplicate/*genetics, Genes, Insect/*genetics, Genetic Variation, Likelihood Functions, Phylogeny, Time Factors}, isbn = {0016-6731 (Print)0016-6731 (Linking)}, author = {Rogers, R. L. and Bedford, T. and Hartl, D. L.} } @article {539686, title = {Glycophorin B is the erythrocyte receptor of Plasmodium falciparum erythrocyte-binding ligand, EBL-1}, journal = {Proc Natl Acad Sci U S A}, volume = {106}, number = {13}, year = {2009}, note = {

Mayer, D C GhislaineCofie, JoannJiang, LubinHartl, Daniel LTracy, ErinKabat, JurajMendoza, Laurence HMiller, Louis Heng2009/03/13 09:00Proc Natl Acad Sci U S A. 2009 Mar 31;106(13):5348-52. doi: 10.1073/pnas.0900878106. Epub 2009 Mar 11.

}, month = {Mar 31}, pages = {5348-52}, abstract = {

In the war against Plasmodium, humans have evolved to eliminate or modify proteins on the erythrocyte surface that serve as receptors for parasite invasion, such as the Duffy blood group, a receptor for Plasmodium vivax, and the Gerbich-negative modification of glycophorin C for Plasmodium falciparum. In turn, the parasite counters with expansion and diversification of ligand families. The high degree of polymorphism in glycophorin B found in malaria-endemic regions suggests that it also may be a receptor for Plasmodium, but, to date, none has been identified. We provide evidence from erythrocyte-binding that glycophorin B is a receptor for the P. falciparum protein EBL-1, a member of the Duffy-binding-like erythrocyte-binding protein (DBL-EBP) receptor family. The erythrocyte-binding domain, region 2 of EBL-1, expressed on CHO-K1 cells, bound glycophorin B(+) but not glycophorin B-null erythrocytes. In addition, glycophorin B(+) but not glycophorin B-null erythrocytes adsorbed native EBL-1 from the P. falciparum culture supernatants. Interestingly, the Efe pygmies of the Ituri forest in the Democratic Republic of the Congo have the highest gene frequency of glycophorin B-null in the world, raising the possibility that the DBL-EBP family may have expanded in response to the high frequency of glycophorin B-null in the population.

}, keywords = {Animals, Antigens, Protozoan/*physiology, Erythrocytes/metabolism/*parasitology, Glycophorin/genetics/*metabolism, Humans, Ligands, Molecular Sequence Data, Plasmodium falciparum/*pathogenicity, Polymorphism, Genetic, Protein Binding, Protozoan Proteins/*physiology, Receptors, Cell Surface/*physiology}, isbn = {1091-6490 (Electronic)0027-8424 (Linking)}, author = {Mayer, D. C. and Cofie, J. and Jiang, L. and Hartl, D. L. and Tracy, E. and Kabat, J. and Mendoza, L. H. and Miller, L. H.} } @article {538561, title = {Optimization of gene expression by natural selection}, journal = {Proc Natl Acad Sci U S A}, volume = {106}, number = {4}, year = {2009}, note = {

Bedford, TrevorHartl, Daniel LengGM065169/GM/NIGMS NIH HHS/GM084236/GM/NIGMS NIH HHS/Research Support, N.I.H., ExtramuralResearch Support, U.S. Gov{\textquoteright}t, Non-P.H.S.2009/01/14 09:00Proc Natl Acad Sci U S A. 2009 Jan 27;106(4):1133-8. doi: 10.1073/pnas.0812009106. Epub 2009 Jan 12.

}, month = {Jan 27}, pages = {1133-8}, abstract = {

It is generally assumed that stabilizing selection promoting a phenotypic optimum acts to shape variation in quantitative traits across individuals and species. Although gene expression represents an intensively studied molecular phenotype, the extent to which stabilizing selection limits divergence in gene expression remains contentious. In this study, we present a theoretical framework for the study of stabilizing and directional selection using data from between-species divergence of continuous traits. This framework, based upon Brownian motion, is analytically tractable and can be used in maximum-likelihood or Bayesian parameter estimation. We apply this model to gene-expression levels in 7 species of Drosophila, and find that gene-expression divergence is substantially curtailed by stabilizing selection. However, we estimate the selective effect, s, of gene-expression change to be very small, approximately equal to Ns for a change of one standard deviation, where N is the effective population size. These findings highlight the power of natural selection to shape phenotype, even when the fitness effects of mutations are in the nearly neutral range.

}, keywords = {*Gene Expression, *Selection, Genetic, Animals, Drosophila Proteins/genetics/metabolism, Drosophila/*genetics, Evolution, Molecular, Genetic Variation, Models, Genetic}, isbn = {1091-6490 (Electronic)0027-8424 (Linking)}, author = {Bedford, T. and Hartl, D. L.} } @article {539971, title = {Population genomic inferences from sparse high-throughput sequencing of two populations of Drosophila melanogaster}, journal = {Genome Biol Evol}, volume = {1}, year = {2009}, note = {

Sackton, Timothy BKulathinal, Rob JBergman, Casey MQuinlan, Aaron RDopman, Erik BCarneiro, MauricioMarth, Gabor THartl, Daniel LClark, Andrew GengR01 AI064950/AI/NIAID NIH HHS/R01 AI064950-04/AI/NIAID NIH HHS/R01 HG004719/HG/NHGRI NIH HHS/R01 HG004719-01/HG/NHGRI NIH HHS/R01 HG004719-02/HG/NHGRI NIH HHS/R01 HG004719-02S1/HG/NHGRI NIH HHS/R01 HG004719-03/HG/NHGRI NIH HHS/R01 HG004719-04/HG/NHGRI NIH HHS/England2009/01/01 00:00Genome Biol Evol. 2009 Nov 18;1:449-65. doi: 10.1093/gbe/evp048.

}, pages = {449-65}, abstract = {

Short-read sequencing techniques provide the opportunity to capture genome-wide sequence data in a single experiment. A current challenge is to identify questions that shallow-depth genomic data can address successfully and to develop corresponding analytical methods that are statistically sound. Here, we apply the Roche/454 platform to survey natural variation in strains of Drosophila melanogaster from an African (n = 3) and a North American (n = 6) population. Reads were aligned to the reference D. melanogaster genomic assembly, single nucleotide polymorphisms were identified, and nucleotide variation was quantified genome wide. Simulations and empirical results suggest that nucleotide diversity can be accurately estimated from sparse data with as little as 0.2x coverage per line. The unbiased genomic sampling provided by random short-read sequencing also allows insight into distributions of transposable elements and copy number polymorphisms found within populations and demonstrates that short-read sequencing methods provide an efficient means to quantify variation in genome organization and content. Continued development of methods for statistical inference of shallow-depth genome-wide sequencing data will allow such sparse, partial data sets to become the norm in the emerging field of population genomics.

}, isbn = {1759-6653 (Electronic)1759-6653 (Linking)}, author = {Sackton, T. B. and Kulathinal, R. J. and Bergman, C. M. and Quinlan, A. R. and Dopman, E. B. and Carneiro, M. and Marth, G. T. and Hartl, D. L. and Clark, A. G.} } @article {539651, title = {Stepwise acquisition of pyrimethamine resistance in the malaria parasite}, journal = {Proc Natl Acad Sci U S A}, volume = {106}, number = {29}, year = {2009}, note = {

Lozovsky, Elena RChookajorn, ThanatBrown, Kyle MImwong, MallikaShaw, Philip JKamchonwongpaisan, SumaleeNeafsey, Daniel EWeinreich, Daniel MHartl, Daniel LengMRG5080418/PHS HHS/R01GM079536/GM/NIGMS NIH HHS/Howard Hughes Medical Institute/Research Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov{\textquoteright}t2009/07/10 09:00Proc Natl Acad Sci U S A. 2009 Jul 21;106(29):12025-30. doi: 10.1073/pnas.0905922106. Epub 2009 Jul 8.

}, month = {Jul 21}, pages = {12025-30}, abstract = {

The spread of high-level pyrimethamine resistance in Africa threatens to curtail the therapeutic lifetime of antifolate antimalarials. We studied the possible evolutionary pathways in the evolution of pyrimethamine resistance using an approach in which all possible mutational intermediates were created by site-directed mutagenesis and assayed for their level of drug resistance. The coding sequence for dihydrofolate reductase (DHFR) from the malaria parasite Plasmodium falciparum was mutagenized, and tests were carried out in Escherichia coli under conditions in which the endogenous bacterial enzyme was selectively inhibited. We studied 4 key amino acid replacements implicated in pyrimethamine resistance: N51I, C59R, S108N, and I164L. Using empirical estimates of the mutational spectrum in P. falciparum and probabilities of fixation based on the relative levels of resistance, we found that the predicted favored pathways of drug resistance are consistent with those reported in previous kinetic studies, as well as DHFR polymorphisms observed in natural populations. We found that 3 pathways account for nearly 90\% of the simulated realizations of the evolution of pyrimethamine resistance. The most frequent pathway (S108N and then C59R, N51I, and I164L) accounts for more than half of the simulated realizations. Our results also suggest an explanation for why I164L is detected in Southeast Asia and South America, but not at significant frequencies in Africa.

}, keywords = {Alleles, Animals, Biological Assay, Drug Resistance/*drug effects, Evolution, Molecular, Inhibitory Concentration 50, Malaria, Falciparum/*parasitology, Parasites/drug effects/enzymology/*genetics/growth \& development, Plasmodium falciparum/drug effects/enzymology/*genetics/growth \& development, Polymorphism, Genetic/drug effects, Pyrimethamine/*pharmacology, Tetrahydrofolate Dehydrogenase/genetics}, isbn = {1091-6490 (Electronic)0027-8424 (Linking)}, author = {Lozovsky, E. R. and Chookajorn, T. and Brown, K. M. and Imwong, M. and Shaw, P. J. and Kamchonwongpaisan, S. and Neafsey, D. E. and Weinreich, D.M. and Hartl, D. L.} } @article {538656, title = {Temporal constraints on the incorporation of regulatory mutants in evolutionary pathways}, journal = {Mol Biol Evol}, volume = {26}, number = {11}, year = {2009}, note = {

Brown, Kyle MDepristo, Mark AWeinreich, Daniel MHartl, Daniel LengGM079536/GM/NIGMS NIH HHS/R01 GM079536/GM/NIGMS NIH HHS/Research Support, N.I.H., ExtramuralResearch Support, U.S. Gov{\textquoteright}t, Non-P.H.S.2009/07/16 09:00Mol Biol Evol. 2009 Nov;26(11):2455-62. doi: 10.1093/molbev/msp151. Epub 2009 Jul 14.

}, month = {Nov}, pages = {2455-62}, abstract = {

Understanding the molecular details of the sequence of events in multistep evolutionary pathways can reveal the extent to which natural selection exploits regulatory mutations affecting expression, amino acid replacements affecting the active site, amino acid replacements affecting protein folding or stability, or variations affecting gene copy number. In experimentally exploring the adaptive landscape of the evolution of resistance to beta-lactam antibiotics in enteric bacteria, we noted that a regulatory mutation that increases beta-lactamase expression by about 2-fold has a very strong tendency to be fixed at or near the end of the evolutionary pathway. This pattern contrasts with previous experiments selecting for the utilization of novel substrates, in which regulatory mutations that increase expression are often fixed early in the process. To understand the basis of the difference, we carried out experiments in which the expression of beta-lactamase was under the control of a tunable arabinose promoter. We find that the fitness effect of an increase in gene expression is highly dependent on the catalytic activity of the coding sequence. An increase in expression of an inefficient enzyme has a negligible effect on drug resistance; however, the effect of an increase in expression of an efficient enzyme is very large. The contrast in the temporal incorporation of regulatory mutants between antibiotic resistance and the utilization of novel substrates is related to the nature of the function that relates enzyme activity to fitness. A mathematical model of beta-lactam resistance is examined in detail and shown to be consistent with the observed results.

}, keywords = {*Evolution, Molecular, beta-Lactamases/genetics, Directed Molecular Evolution, Drug Resistance, Microbial/genetics, Escherichia coli/*classification/*genetics, Kinetics, Microbial Sensitivity Tests, Mutation/*genetics}, isbn = {1537-1719 (Electronic)0737-4038 (Linking)}, author = {Brown, K. M. and Depristo, M. A. and Weinreich, D.M. and Hartl, D. L.} } @article {538661, title = {Cascading transcriptional effects of a naturally occurring frameshift mutation in Saccharomyces cerevisiae}, journal = {Mol Ecol}, volume = {17}, number = {12}, year = {2008}, note = {

Brown, Kyle MLandry, Christian RHartl, Daniel LCavalieri, DuccioengResearch Support, Non-U.S. Gov{\textquoteright}tResearch Support, U.S. Gov{\textquoteright}t, Non-P.H.S.England2008/04/22 09:00Mol Ecol. 2008 Jun;17(12):2985-97. doi: 10.1111/j.1365-294X.2008.03765.x. Epub 2008 Apr 18.

}, month = {Jun}, pages = {2985-97}, abstract = {

Gene-expression variation in natural populations is widespread, and its phenotypic effects can be acted upon by natural selection. Only a few naturally segregating genetic differences associated with expression variation have been identified at the molecular level. We have identified a single nucleotide insertion in a vineyard isolate of Saccharomyces cerevisiae that has cascading effects through the gene-expression network. This allele is responsible for about 45\% (103/230) of the genes that show differential gene expression among the homozygous diploid progeny produced by a vineyard isolate. Using isogenic laboratory strains, we confirm that this allele causes dramatic differences in gene-expression levels of key genes involved in amino acid biosynthesis. The mutation is a frameshift mutation in a mononucleotide run of eight consecutive T{\textquoteright}s in the coding region of the gene SSY1, which encodes a key component of a plasma-membrane sensor of extracellular amino acids. The potentially high rate of replication slippage of this mononucleotide repeat, combined with its relatively mild effects on growth rate in heterozygous genotypes, is sufficient to account for the persistence of this phenotype at low frequencies in natural populations.

}, keywords = {*Frameshift Mutation, *Transcription, Genetic, Alleles, Gene Expression Regulation, Fungal, Gene Frequency, Genetic Complementation Test, Genotype, Intracellular Signaling Peptides and Proteins, Membrane Proteins/*genetics, Oligonucleotide Array Sequence Analysis, Phenotype, Saccharomyces cerevisiae Proteins/*genetics, Saccharomyces cerevisiae/*genetics/growth \& development, Sequence Analysis, DNA}, isbn = {1365-294X (Electronic)0962-1083 (Linking)}, author = {Brown, K. M. and Landry, C. R. and Hartl, D. L. and Cavalieri, D.} } @article {539531, title = {Dominance and the evolutionary accumulation of cis- and trans-effects on gene expression}, journal = {Proc Natl Acad Sci U S A}, volume = {105}, number = {38}, year = {2008}, note = {

Lemos, BernardoAraripe, Luciana OFontanillas, PierreHartl, Daniel LengGM068465/GM/NIGMS NIH HHS/Research Support, N.I.H., Extramural2008/09/16 09:00Proc Natl Acad Sci U S A. 2008 Sep 23;105(38):14471-6. doi: 10.1073/pnas.0805160105. Epub 2008 Sep 12.

}, month = {Sep 23}, pages = {14471-6}, abstract = {

Gene expression levels appear to be under pervasive stabilizing selection. Yet the genetic architecture underlying abundant gene expression diversity within and between populations remains elusive. Here, we investigated the role of dominance in the segregation of cis- and trans-regulation within and between populations. We used chromosome substitution lines of Drosophila melanogaster to show that (i) \>70\% of the genes that are differentially expressed between two homozygous lines are masked in the heterozygous, suggesting that one of the substituted chromosomes contains a recessive allele; (ii) such large masking is already obtained with heterozygous chromosomes originating from the same population, with the time of divergence between chromosomes in heterozygous lines making only a small but significant contribution to the masking of variation observed in homozygous lines; (iii) variation in gene expression due to trans-regulation is biased toward greater deviations from additivity because of recessive and dominant alleles, whereas variation due to cis-regulation shows higher additivity; and (iv) genetic divergence between second chromosomes is associated with increased cis-regulation, whereas the level of trans-regulation shows little increase over the time scale studied. Our results indicate that cis-acting alleles may be preferentially fixed by positive natural selection because of their higher additivity, and that the disruption of gene expression by recessive variation with pervasive trans-effects may be important for understanding gene expression variation within populations. We suggest that widespread regulatory effects of recessive low-frequency homozygous variation may provide a general mechanism mediating disease phenotypes and the genetic load of natural populations.

}, keywords = {*Evolution, Molecular, *Genes, Dominant, Animals, Chromosomes/genetics, Drosophila melanogaster/*genetics, Gene Expression Regulation/*genetics, Genetic Variation, Genotype, Heterozygote, Homozygote, Phenotype}, isbn = {1091-6490 (Electronic)0027-8424 (Linking)}, author = {Lemos, B. and Araripe, L. O. and Fontanillas, P. and Hartl, D. L.} } @article {538541, title = {Effects of X-linkage and sex-biased gene expression on the rate of adaptive protein evolution in Drosophila}, journal = {Mol Biol Evol}, volume = {25}, number = {8}, year = {2008}, note = {

Baines, John FSawyer, Stanley AHartl, Daniel LParsch, JohnengGM61351/GM/NIGMS NIH HHS/GM68465/GM/NIGMS NIH HHS/Comparative StudyResearch Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov{\textquoteright}tResearch Support, U.S. Gov{\textquoteright}t, Non-P.H.S.2008/05/15 09:00Mol Biol Evol. 2008 Aug;25(8):1639-50. doi: 10.1093/molbev/msn111. Epub 2008 May 13.

}, month = {Aug}, pages = {1639-50}, abstract = {

Patterns of polymorphism and divergence in Drosophila protein-coding genes suggest that a considerable fraction of amino acid differences between species can be attributed to positive selection and that genes with sex-biased expression, that is, those expressed predominantly in one sex, have especially high rates of adaptive evolution. Previous studies, however, have been restricted to autosomal sex-biased genes and, thus, do not provide a complete picture of the evolutionary forces acting on sex-biased genes across the genome. To determine the effects of X-linkage on sex-biased gene evolution, we surveyed DNA sequence polymorphism and divergence in 45 X-linked genes, including 17 with male-biased expression, 13 with female-biased expression, and 15 with equal expression in the 2 sexes. Using both single- and multilocus tests for selection, we found evidence for adaptive evolution in both groups of sex-biased genes. The signal of adaptive evolution was particularly strong for X-linked male-biased genes. A comparison with data from 91 autosomal genes revealed a "fast-X" effect, in which the rate of adaptive evolution was greater for X-linked than for autosomal genes. This effect was strongest for male-biased genes but could be seen in the other groups as well. A genome-wide analysis of coding sequence divergence that accounted for sex-biased expression also uncovered a fast-X effect for male-biased and unbiased genes, suggesting that recessive beneficial mutations play an important role in adaptation.

}, keywords = {*Evolution, Molecular, *Gene Expression, *Polymorphism, Genetic, Adaptation, Biological/*genetics, Animals, Base Sequence, Drosophila Proteins/*genetics/metabolism, Drosophila/*genetics, Female, Genes, X-Linked/*genetics, Male, Molecular Sequence Data, Sequence Analysis, DNA, Sex Factors}, isbn = {1537-1719 (Electronic)0737-4038 (Linking)}, author = {Baines, J. F. and Sawyer, S. A. and Hartl, D. L. and Parsch, J.} } @article {539951, title = {Evolution of allelic dimorphism in malarial surface antigens}, journal = {Heredity (Edinb)}, volume = {100}, number = {2}, year = {2008}, note = {

Roy, S WFerreira, M UHartl, D LengResearch Support, Non-U.S. Gov{\textquoteright}tReviewEngland2006/10/06 09:00Heredity (Edinb). 2008 Feb;100(2):103-10. Epub 2006 Oct 4.

}, month = {Feb}, pages = {103-10}, abstract = {

The extensive sequence variation in most surface antigens of Plasmodium falciparum is one of the major factors why clinical immunity to malaria develops only after repeated infections with the same species over several years. For some P. falciparum surface antigens, all observed alleles clearly fall into two allelic classes, with divergence between classes dwarfing divergence within classes. We discuss the ways in which such allelic dimorphism deviates from the expected shape of the genealogy of genes under either neutral evolution or standard balancing selection, and present a simple test, based on coalescent theory, to detect this deviation in samples of DNA sequences. We review previous hypotheses for the origin and evolution of allelic dimorphism in malarial antigens and discuss the difficulties of explaining the available data under these proposals. We conclude by offering several possible classes of explanations for allelic dimorphism, which are worthy of further theoretical and empirical exploration.

}, keywords = {*Antigenic Variation, *Evolution, Molecular, *Polymorphism, Genetic, Alleles, Animals, Antigens, Protozoan/*genetics, Humans, Merozoite Surface Protein 1/genetics, Phylogeny, Plasmodium falciparum/genetics/*immunology}, isbn = {1365-2540 (Electronic)0018-067X (Linking)}, author = {Roy, S. W. and Ferreira, M. U. and Hartl, D. L.} } @article {539426, title = {Extensive microsatellite diversity in the human malaria parasite Plasmodium vivax}, journal = {Gene}, volume = {410}, number = {1}, year = {2008}, note = {

Karunaweera, Nadira DFerreira, Marcelo UMunasinghe, AnushaBarnwell, John WCollins, William EKing, Christopher LKawamoto, FumihikoHartl, Daniel LWirth, Dyann FengR01 GM 061351/GM/NIGMS NIH HHS/Research Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov{\textquoteright}tResearch Support, U.S. Gov{\textquoteright}t, Non-P.H.S.Netherlands2008/01/30 09:00Gene. 2008 Feb 29;410(1):105-12. doi: 10.1016/j.gene.2007.11.022. Epub 2008 Jan 15.

}, month = {Feb 29}, pages = {105-12}, abstract = {

The population structure of Plasmodium vivax remains elusive. The markers of choice for large-scale population genetic studies of eukaryotes, short tandem repeats known as microsatellites, have been recently reported to be less polymorphic in P. vivax. Here we investigate the microsatellite diversity and geographic structure in P. vivax, at both local and global levels, using 14 new markers consisting of tri- or tetranucleotide repeats. The local-level analysis, which involved 50 field isolates from Sri Lanka, revealed unexpectedly high diversity (average virtual heterozygosity [H(E)], 0.807) and significant multilocus linkage disequilibrium in this region of low malaria endemicity. Multiple-clone infections occurred in 60\% of isolates sampled in 2005. The global-level analysis of field isolates or monkey-adapted strains identified 150 unique haplotypes among 164 parasites from four continents. Individual P. vivax isolates could not be unambiguously assigned to geographic populations. For example, we found relatively low divergence among parasites from Central America, Africa, Southeast Asia and Oceania, but substantial differentiation between parasites from the same continent (South Asia and Southeast Asia) or even from the same country (Brazil). Parasite relapses, which may extend the duration of P. vivax carriage in humans, are suggested to facilitate the spread of strains across continents, breaking down any pre-existing geographic structure.

}, keywords = {Animals, DNA, Protozoan/genetics, Linkage Disequilibrium, Microsatellite Repeats/*genetics, Plasmodium vivax/*genetics}, isbn = {0378-1119 (Print)0378-1119 (Linking)}, author = {Karunaweera, N. D. and Ferreira, M. U. and Munasinghe, A. and Barnwell, J. W. and Collins, W. E. and King, C. L. and Kawamoto, F. and Hartl, D. L. and Wirth, DF} } @article {539761, title = {Genome-wide SNP genotyping highlights the role of natural selection in Plasmodium falciparum population divergence}, journal = {Genome Biol}, volume = {9}, number = {12}, year = {2008}, note = {

Neafsey, Daniel ESchaffner, Stephen FVolkman, Sarah KPark, DanielMontgomery, PhilipMilner, Danny A JrLukens, AmandaRosen, DavidDaniels, RachelHoude, NathanCortese, Joseph FTyndall, ErinGates, CaseyStange-Thomann, NicoleSarr, OusmaneNdiaye, DaoudaNdir, OmarMboup, SoulyemaneFerreira, Marcelo UMoraes, Sandra do LagoDash, Aditya PChitnis, Chetan EWiegand, Roger CHartl, Daniel LBirren, Bruce WLander, Eric SSabeti, Pardis CWirth, Dyann FengU54 RR020278/RR/NCRR NIH HHS/Research Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov{\textquoteright}tEngland2008/12/17 09:00Genome Biol. 2008;9(12):R171. doi: 10.1186/gb-2008-9-12-r171. Epub 2008 Dec 15.

}, pages = {R171}, abstract = {

BACKGROUND: The malaria parasite Plasmodium falciparum exhibits abundant genetic diversity, and this diversity is key to its success as a pathogen. Previous efforts to study genetic diversity in P. falciparum have begun to elucidate the demographic history of the species, as well as patterns of population structure and patterns of linkage disequilibrium within its genome. Such studies will be greatly enhanced by new genomic tools and recent large-scale efforts to map genomic variation. To that end, we have developed a high throughput single nucleotide polymorphism (SNP) genotyping platform for P. falciparum. RESULTS: Using an Affymetrix 3,000 SNP assay array, we found roughly half the assays (1,638) yielded high quality, 100\% accurate genotyping calls for both major and minor SNP alleles. Genotype data from 76 global isolates confirm significant genetic differentiation among continental populations and varying levels of SNP diversity and linkage disequilibrium according to geographic location and local epidemiological factors. We further discovered that nonsynonymous and silent (synonymous or noncoding) SNPs differ with respect to within-population diversity, inter-population differentiation, and the degree to which allele frequencies are correlated between populations. CONCLUSIONS: The distinct population profile of nonsynonymous variants indicates that natural selection has a significant influence on genomic diversity in P. falciparum, and that many of these changes may reflect functional variants deserving of follow-up study. Our analysis demonstrates the potential for new high-throughput genotyping technologies to enhance studies of population structure, natural selection, and ultimately enable genome-wide association studies in P. falciparum to find genes underlying key phenotypic traits.

}, keywords = {*Polymorphism, Single Nucleotide, *Selection, Genetic, Animals, Gene Frequency, Genome-Wide Association Study, Phylogeny, Plasmodium falciparum/classification/*genetics}, isbn = {1465-6914 (Electronic)1465-6906 (Linking)}, author = {Neafsey, D. E. and Schaffner, S. F. and Volkman, S. K. and Park, D. and Montgomery, P. and Milner, D. A., Jr. and Lukens, A. and Rosen, D. and Daniels, R. and Houde, N. and Cortese, J. F. and Tyndall, E. and Gates, C. and Stange-Thomann, N. and Sarr, O. and Ndiaye, D. and Ndir, O. and Mboup, S. and Ferreira, M. U. and Moraes Sdo, L. and Dash, A. P. and Chitnis, C. E. and Wiegand, R. C. and Hartl, D. L. and Birren, B. W. and Lander, E. S. and Sabeti, P. C. and Wirth, DF} } @article {539666, title = {A genome-wide view of the spectrum of spontaneous mutations in yeast}, journal = {Proc Natl Acad Sci U S A}, volume = {105}, number = {27}, year = {2008}, note = {

Lynch, MichaelSung, WayMorris, KrystalynneCoffey, NicoleLandry, Christian RDopman, Erik BDickinson, W JosephOkamoto, KazufusaKulkarni, ShilpaHartl, Daniel LThomas, W KelleyengGM068465/GM/NIGMS NIH HHS/GM36827/GM/NIGMS NIH HHS/R01 GM036827/GM/NIGMS NIH HHS/Research Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov{\textquoteright}t2008/06/28 09:00Proc Natl Acad Sci U S A. 2008 Jul 8;105(27):9272-7. doi: 10.1073/pnas.0803466105. Epub 2008 Jun 26.

}, month = {Jul 8}, pages = {9272-7}, abstract = {

The mutation process ultimately defines the genetic features of all populations and, hence, has a bearing on a wide range of issues involving evolutionary genetics, inheritance, and genetic disorders, including the predisposition to cancer. Nevertheless, formidable technical barriers have constrained our understanding of the rate at which mutations arise and the molecular spectrum of their effects. Here, we report on the use of complete-genome sequencing in the characterization of spontaneously arising mutations in the yeast Saccharomyces cerevisiae. Our results confirm some findings previously obtained by indirect methods but also yield numerous unexpected findings, in particular a very high rate of point mutation and skewed distribution of base-substitution types in the mitochondrion, a very high rate of segmental duplication and deletion in the nuclear genome, and substantial deviations in the mutational profile among various model organisms.

}, keywords = {Base Sequence, Cell Division, Chromosomes, Fungal/genetics, DNA, Mitochondrial/genetics, Genome, Fungal/*genetics, Microsatellite Repeats/genetics, Mutation/*genetics, Nucleotides, Ploidies, Saccharomyces cerevisiae/cytology/*genetics}, isbn = {1091-6490 (Electronic)0027-8424 (Linking)}, author = {Lynch, M. and Sung, W. and Morris, K. and Coffey, N. and Landry, C. R. and Dopman, E. B. and Dickinson, W. J. and Okamoto, K. and Kulkarni, S. and Hartl, D. L. and WK Thomas} } @article {538556, title = {Overdispersion of the molecular clock: temporal variation of gene-specific substitution rates in Drosophila}, journal = {Mol Biol Evol}, volume = {25}, number = {8}, year = {2008}, note = {

Bedford, TrevorHartl, Daniel LengGM079536/GM/NIGMS NIH HHS/Comparative StudyResearch Support, N.I.H., ExtramuralResearch Support, U.S. Gov{\textquoteright}t, Non-P.H.S.2008/05/16 09:00Mol Biol Evol. 2008 Aug;25(8):1631-8. doi: 10.1093/molbev/msn112. Epub 2008 May 13.

}, month = {Aug}, pages = {1631-8}, abstract = {

Simple models of molecular evolution assume that sequences evolve by a Poisson process in which nucleotide or amino acid substitutions occur as rare independent events. In these models, the expected ratio of the variance to the mean of substitution counts equals 1, and substitution processes with a ratio greater than 1 are called overdispersed. Comparing the genomes of 10 closely related species of Drosophila, we extend earlier evidence for overdispersion in amino acid replacements as well as in four-fold synonymous substitutions. The observed deviation from the Poisson expectation can be described as a linear function of the rate at which substitutions occur on a phylogeny, which implies that deviations from the Poisson expectation arise from gene-specific temporal variation in substitution rates. Amino acid sequences show greater temporal variation in substitution rates than do four-fold synonymous sequences. Our findings provide a general phenomenological framework for understanding overdispersion in the molecular clock. Also, the presence of substantial variation in gene-specific substitution rates has broad implications for work in phylogeny reconstruction and evolutionary rate estimation.

}, keywords = {*Evolution, Molecular, *Models, Genetic, *Phylogeny, Amino Acid Sequence, Amino Acid Substitution/*genetics, Animals, Computational Biology, Drosophila/*genetics, Sequence Alignment, Species Specificity}, isbn = {1537-1719 (Electronic)0737-4038 (Linking)}, author = {Bedford, T. and Hartl, D. L.} } @article {538566, title = {Overdispersion of the molecular clock varies between yeast, Drosophila and mammals}, journal = {Genetics}, volume = {179}, number = {2}, year = {2008}, note = {

Bedford, TrevorWapinski, IlanHartl, Daniel LengGM079536/GM/NIGMS NIH HHS/Comparative StudyResearch Support, N.I.H., ExtramuralResearch Support, U.S. Gov{\textquoteright}t, Non-P.H.S.2008/05/29 09:00Genetics. 2008 Jun;179(2):977-84. doi: 10.1534/genetics.108.089185. Epub 2008 May 27.

}, month = {Jun}, pages = {977-84}, abstract = {

Although protein evolution can be approximated as a "molecular evolutionary clock," it is well known that sequence change departs from a clock-like Poisson expectation. Through studying the deviations from a molecular clock, insight can be gained into the forces shaping evolution at the level of proteins. Generally, substitution patterns that show greater variance than the Poisson expectation are said to be "overdispersed." Overdispersion of sequence change may result from temporal variation in the rate at which amino acid substitutions occur on a phylogeny. By comparing the genomes of four species of yeast, five species of Drosophila, and five species of mammals, we show that the extent of overdispersion shows a strong negative correlation with the effective population size of these organisms. Yeast proteins show very little overdispersion, while mammalian proteins show substantial overdispersion. Additionally, X-linked genes, which have reduced effective population size, have gene products that show increased overdispersion in both Drosophila and mammals. Our research suggests that mutational robustness is more pervasive in organisms with large population sizes and that robustness acts to stabilize the molecular evolutionary clock of sequence change.

}, keywords = {*Evolution, Molecular, Amino Acid Substitution, Animals, Drosophila Proteins/genetics, Drosophila/classification/*genetics, Female, Fungal Proteins/genetics, Humans, Likelihood Functions, Linear Models, Male, Mammals/classification/*genetics, Models, Genetic, Phylogeny, Saccharomyces/classification/*genetics, Selection, Genetic, Species Specificity, Time Factors, X Chromosome/genetics}, isbn = {0016-6731 (Print)0016-6731 (Linking)}, author = {Bedford, T. and Wapinski, I. and Hartl, D. L.} } @article {538506, title = {Patterns of polymorphism in genomic regions flanking three highly polymorphic surface antigens in Plasmodium falciparum}, journal = {Mol Biochem Parasitol}, volume = {159}, number = {1}, year = {2008}, note = {

Amodu, Olukemi KHartl, Daniel LRoy, Scott WilliamengGM079536/GM/NIGMS NIH HHS/GM61351/GM/NIGMS NIH HHS/Research Support, N.I.H., ExtramuralNetherlands2008/02/23 09:00Mol Biochem Parasitol. 2008 May;159(1):1-6. doi: 10.1016/j.molbiopara.2007.12.004. Epub 2007 Dec 15.

}, month = {May}, pages = {1-6}, abstract = {

Many surface antigens of the human malaria parasite Plasmodium falciparum show extraordinary diversity, with different alleles being so divergent as to be unalignable in some coding regions. To better understand the population history and modes of selection on such loci, we sequenced genomic regions flanking the highly polymorphic genes merozoite surface protein-1, merozoite surface protein-2, and circumsporozoite protein, from reference isolates of P. falciparum. Diversity was much lower in genomic flanking regions than in the coding sequences. Average pairwise nucleotide diversity for these regions was 0.00088, similar to other genomic regions not thought to be evolving under balancing selection, suggesting against balancing selection acting on promoter regions of these genes. Most observed polymorphisms were singletons. A higher ratio of SNPs to indels than previously reported for P. falciparum was observed. An 11 bp repeat upstream of msp2 showed an intriguing pattern of polymorphism possibly suggestive of purifying selection on total allele length.

}, keywords = {*Polymorphism, Genetic, Animals, Antigens, Protozoan/chemistry/*genetics, Base Sequence, Genetics, Population, Humans, Merozoite Surface Protein 1/chemistry/*genetics, Molecular Sequence Data, Plasmodium falciparum/*genetics, Polymorphism, Single Nucleotide, Protozoan Proteins/chemistry/*genetics, Sequence Analysis, DNA}, isbn = {0166-6851 (Print)0166-6851 (Linking)}, author = {Amodu, O. K. and Hartl, D. L. and Roy, S. W.} } @article {539536, title = {Polymorphic Y chromosomes harbor cryptic variation with manifold functional consequences}, journal = {Science}, volume = {319}, number = {5859}, year = {2008}, note = {

Lemos, BernardoAraripe, Luciana OHartl, Daniel LengGM065169/GM/NIGMS NIH HHS/GM068465/GM/NIGMS NIH HHS/Research Support, N.I.H., ExtramuralNew York, N.Y.2008/01/05 09:00Science. 2008 Jan 4;319(5859):91-3. doi: 10.1126/science.1148861.

}, month = {Jan 4}, pages = {91-3}, abstract = {

The paucity of polymorphisms in single-copy genes on the Y chromosome of Drosophila contrasts with data indicating that this chromosome has polymorphic phenotypic effects on sex ratio, temperature sensitivity, behavior, and fitness. We show that the Y chromosome of D. melanogaster harbors substantial genetic diversity in the form of polymorphisms for genetic elements that differentially affect the expression of hundreds of X-linked and autosomal genes. The affected genes are more highly expressed in males, more meagerly expressed in females, and more highly divergent between species. Functionally, they affect microtubule stability, lipid and mitochondrial metabolism, and the thermal sensitivity of spermatogenesis. Our findings provide a mechanism for adaptive phenotypic variation associated with the Y chromosome.

}, keywords = {*Gene Expression Regulation, *Polymorphism, Genetic, Animals, Biological Evolution, Climate, DNA Transposable Elements, Drosophila melanogaster/*genetics/physiology, Drosophila/*genetics/physiology, Epigenesis, Genetic, Female, Genes, Insect, Genetic Linkage, Genetic Variation, Heterochromatin/genetics, Male, Spermatogenesis, Temperature, Y Chromosome/*genetics}, isbn = {1095-9203 (Electronic)0036-8075 (Linking)}, author = {Lemos, B. and Araripe, L. O. and Hartl, D. L.} } @article {538831, title = {Epigenetic memory at malaria virulence genes}, journal = {Proc Natl Acad Sci U S A}, volume = {104}, number = {3}, year = {2007}, note = {

Chookajorn, ThanatDzikowski, RonFrank, MatthiasLi, FelomenaJiwani, Alisha ZHartl, Daniel LDeitsch, Kirk WengAI 52390/AI/NIAID NIH HHS/Research Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov{\textquoteright}t2007/01/09 09:00Proc Natl Acad Sci U S A. 2007 Jan 16;104(3):899-902. Epub 2007 Jan 5.

}, month = {Jan 16}, pages = {899-902}, abstract = {

During its red blood cell stage, the malaria parasite Plasmodium falciparum can switch its variant surface proteins (P. falciparum erythrocyte membrane protein 1) to evade the host immune response. The var gene family encodes P. falciparum erythrocyte membrane protein 1, different versions of which have unique binding specificities to various human endothelial surface molecules. Individual parasites each contain approximately 60 var genes at various locations within their chromosomes; however, parasite isolates contain different complements of var genes, thus, the gene family is enormous with a virtually unlimited number of members. A single var gene is expressed by each parasite in a mutually exclusive manner. We report that control of var gene transcription and antigenic variation is associated with a chromatin memory that includes methylation of histone H3 at lysine K9 as an epigenetic mark. We also discuss how gene transcription memory may affect the mechanism of pathogenesis and immune evasion.

}, keywords = {*Gene Expression Regulation, Animals, Chromatin/genetics/metabolism, Epigenesis, Genetic/*genetics, Histones/metabolism, Malaria/immunology/*parasitology, Methylation, Plasmodium falciparum/*genetics/immunology/*pathogenicity, Transcription, Genetic/genetics, Virulence/genetics}, isbn = {0027-8424 (Print)0027-8424 (Linking)}, author = {Chookajorn, T. and Dzikowski, R. and Frank, M. and Li, F. and Jiwani, A. Z. and Hartl, D. L. and Deitsch, K. W.} } @article {539476, title = {Genetic properties influencing the evolvability of gene expression}, journal = {Science}, volume = {317}, number = {5834}, year = {2007}, note = {

Landry, Christian RLemos, BernardoRifkin, Scott ADickinson, W JHartl, Daniel LengResearch Support, Non-U.S. Gov{\textquoteright}tNew York, N.Y.2007/05/26 09:00Science. 2007 Jul 6;317(5834):118-21. Epub 2007 May 24.

}, month = {Jul 6}, pages = {118-21}, abstract = {

Identifying the properties of gene networks that influence their evolution is a fundamental research goal. However, modes of evolution cannot be inferred solely from the distribution of natural variation, because selection interacts with demography and mutation rates to shape polymorphism and divergence. We estimated the effects of naturally occurring mutations on gene expression while minimizing the effect of natural selection. We demonstrate that sensitivity of gene expression to mutations increases with both increasing trans-mutational target size and the presence of a TATA box. Genes with greater sensitivity to mutations are also more sensitive to systematic environmental perturbations and stochastic noise. These results provide a mechanistic basis for gene expression evolvability that can serve as a foundation for realistic models of regulatory evolution.

}, keywords = {*Evolution, Molecular, *Gene Expression, *Gene Regulatory Networks, *Genes, Fungal, *Mutation, Binding Sites, Gene Expression Regulation, Fungal, Genetic Variation, Linear Models, Models, Genetic, Oligonucleotide Array Sequence Analysis, Phenotype, Promoter Regions, Genetic, Saccharomyces cerevisiae/*genetics, Selection, Genetic, TATA Box, Transcription Factors/metabolism, Transcription, Genetic}, isbn = {1095-9203 (Electronic)0036-8075 (Linking)}, author = {Landry, C. R. and Lemos, B. and Rifkin, S. A. and Dickinson, W. J. and Hartl, D. L.} } @article {539471, title = {Genome clashes in hybrids: insights from gene expression}, journal = {Heredity (Edinb)}, volume = {99}, number = {5}, year = {2007}, note = {

Landry, C RHartl, D LRanz, J MengComparative StudyResearch Support, Non-U.S. Gov{\textquoteright}tReviewEngland2007/08/10 09:00Heredity (Edinb). 2007 Nov;99(5):483-93. Epub 2007 Aug 8.

}, month = {Nov}, pages = {483-93}, abstract = {

In interspecific hybrids, novel phenotypes often emerge from the interaction of two divergent genomes. Interactions between the two transcriptional networks are assumed to contribute to these unpredicted new phenotypes by inducing novel patterns of gene expression. Here we provide a review of the recent literature on the accumulation of regulatory incompatibilities. We review specific examples of regulatory incompatibilities reported at particular loci as well as genome-scale surveys of gene expression in interspecific hybrids. Finally, we consider and preview novel technologies that could help decipher how divergent transcriptional networks interact in hybrids between species.

}, keywords = {*Gene Expression Profiling, *Genome, *Hybridization, Genetic, *Transcription, Genetic, Animals, Humans}, isbn = {0018-067X (Print)0018-067X (Linking)}, author = {Landry, C. R. and Hartl, D. L. and Ranz, J. M.} } @article {538991, title = {Genome organization and gene expression shape the transposable element distribution in the Drosophila melanogaster euchromatin}, journal = {PLoS Genet}, volume = {3}, number = {11}, year = {2007}, note = {

Fontanillas, PierreHartl, Daniel LReuter, MaxengResearch Support, Non-U.S. Gov{\textquoteright}t2007/12/18 09:00PLoS Genet. 2007 Nov;3(11):e210. Epub 2007 Oct 10.

}, month = {Nov}, pages = {e210}, abstract = {

The distribution of transposable elements (TEs) in a genome reflects a balance between insertion rate and selection against new insertions. Understanding the distribution of TEs therefore provides insights into the forces shaping the organization of genomes. Past research has shown that TEs tend to accumulate in genomic regions with low gene density and low recombination rate. However, little is known about the factors modulating insertion rates across the genome and their evolutionary significance. One candidate factor is gene expression, which has been suggested to increase local insertion rate by rendering DNA more accessible. We test this hypothesis by comparing the TE density around germline- and soma-expressed genes in the euchromatin of Drosophila melanogaster. Because only insertions that occur in the germline are transmitted to the next generation, we predicted a higher density of TEs around germline-expressed genes than soma-expressed genes. We show that the rate of TE insertions is greater near germline- than soma-expressed genes. However, this effect is partly offset by stronger selection for genome compactness (against excess noncoding DNA) on germline-expressed genes. We also demonstrate that the local genome organization in clusters of coexpressed genes plays a fundamental role in the genomic distribution of TEs. Our analysis shows that-in addition to recombination rate-the distribution of TEs is shaped by the interaction of gene expression and genome organization. The important role of selection for compactness sheds a new light on the role of TEs in genome evolution. Instead of making genomes grow passively, TEs are controlled by the forces shaping genome compactness, most likely linked to the efficiency of gene expression or its complexity and possibly their interaction with mechanisms of TE silencing.

}, keywords = {Animals, Base Sequence, Conserved Sequence, DNA Transposable Elements/*genetics, DNA, Intergenic/genetics, Drosophila melanogaster/*genetics, Euchromatin/*genetics, Gene Expression Regulation/*genetics, Genes, X-Linked, Genome, Insect/*genetics, Germ Cells/metabolism, Introns/genetics, Multigene Family, Transcription, Genetic, Untranslated Regions/genetics}, isbn = {1553-7404 (Electronic)1553-7390 (Linking)}, author = {Fontanillas, P. and Hartl, D. L. and Reuter, M.} } @article {540151, title = {A genome-wide map of diversity in Plasmodium falciparum}, journal = {Nat Genet}, volume = {39}, number = {1}, year = {2007}, note = {

Volkman, Sarah KSabeti, Pardis CDeCaprio, DavidNeafsey, Daniel ESchaffner, Stephen FMilner, Danny A JrDaily, Johanna PSarr, OusmaneNdiaye, DaoudaNdir, OmarMboup, SoulyemaneDuraisingh, Manoj TLukens, AmandaDerr, AlanStange-Thomann, NicoleWaggoner, SkyeOnofrio, RobertZiaugra, LiudaMauceli, EvanGnerre, SanteJaffe, David BZainoun, JoanneWiegand, Roger CBirren, Bruce WHartl, Daniel LGalagan, James ELander, Eric SWirth, Dyann FengComparative StudyResearch Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov{\textquoteright}t2006/12/13 09:00Nat Genet. 2007 Jan;39(1):113-9. Epub 2006 Dec 10.

}, month = {Jan}, pages = {113-9}, abstract = {

Genetic variation allows the malaria parasite Plasmodium falciparum to overcome chemotherapeutic agents, vaccines and vector control strategies and remain a leading cause of global morbidity and mortality. Here we describe an initial survey of genetic variation across the P. falciparum genome. We performed extensive sequencing of 16 geographically diverse parasites and identified 46,937 SNPs, demonstrating rich diversity among P. falciparum parasites (pi = 1.16 x 10(-3)) and strong correlation with gene function. We identified multiple regions with signatures of selective sweeps in drug-resistant parasites, including a previously unidentified 160-kb region with extremely low polymorphism in pyrimethamine-resistant parasites. We further characterized 54 worldwide isolates by genotyping SNPs across 20 genomic regions. These data begin to define population structure among African, Asian and American groups and illustrate the degree of linkage disequilibrium, which extends over relatively short distances in African parasites but over longer distances in Asian parasites. We provide an initial map of genetic diversity in P. falciparum and demonstrate its potential utility in identifying genes subject to recent natural selection and in understanding the population genetics of this parasite.

}, keywords = {*Genetic Variation, *Genome, Protozoan, Africa, Animals, Asia, Central America, Chromosome Mapping/*methods, Genotype, Humans, Phylogeny, Plasmodium falciparum/*genetics, Polymorphism, Single Nucleotide, South America}, isbn = {1061-4036 (Print)1061-4036 (Linking)}, author = {Volkman, S. K. and Sabeti, P. C. and DeCaprio, D. and Neafsey, D. E. and Schaffner, S. F. and Milner, D. A., Jr. and Daily, J. P. and Sarr, O. and Ndiaye, D. and Ndir, O. and Mboup, S. and Duraisingh, M. T. and Lukens, A. and Derr, A. and Stange-Thomann, N. and Waggoner, S. and Onofrio, R. and Ziaugra, L. and Mauceli, E. and Gnerre, S. and Jaffe, D. B. and Zainoun, J. and Wiegand, R. C. and Birren, B. W. and Hartl, D. L. and Galagan, J. E. and Lander, E. S. and Wirth, DF} } @article {540141, title = {Genomic heterogeneity in the density of noncoding single-nucleotide and microsatellite polymorphisms in Plasmodium falciparum}, journal = {Gene}, volume = {387}, number = {1-2}, year = {2007}, note = {

Volkman, Sarah KLozovsky, ElenaBarry, Alyssa EBedford, TrevorBethke, LaraMyrick, AlissaDay, Karen PHartl, Daniel LWirth, Dyann FSawyer, Stanley AengR01 GM061351/GM/NIGMS NIH HHS/Research Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov{\textquoteright}tResearch Support, U.S. Gov{\textquoteright}t, Non-P.H.S.Netherlands2006/09/29 09:00Gene. 2007 Jan 31;387(1-2):1-6. Epub 2006 Aug 14.

}, month = {Jan 31}, pages = {1-6}, abstract = {

The density and distribution of single-nucleotide polymorphisms (SNPs) across the genome has important implications for linkage disequilibrium mapping and association studies, and the level of simple-sequence microsatellite polymorphisms has important implications for the use of oligonucleotide hybridization methods to genotype SNPs. To assess the density of these types of polymorphisms in P. falciparum, we sampled introns and noncoding DNA upstream and downstream of coding regions among a variety of geographically diverse parasites. Across 36,229 base pairs of noncoding sequence representing 41 genetic loci, a total of 307 polymorphisms including 248 polymorphic microsatellites and 39 SNPs were identified. We found a significant excess of microsatellite polymorphisms having a repeat unit length of one or two, compared to those with longer repeat lengths, as well as a nonrandom distribution of SNP polymorphisms. Almost half of the SNPs localized to only three of the 41 genetic loci sampled. Furthermore, we find significant differences in the frequency of polymorphisms across the two chromosomes (2 and 3) examined most extensively, with an excess of SNPs and a surplus of polymorphic microsatellites on chromosome 3 as compared to chromosome 2 (P=0.0001). Furthermore, at some individual genetic loci we also find a nonrandom distribution of polymorphisms between coding and flanking noncoding sequences, where completely monomorphic regions may flank highly polymorphic genes. These data, combined with our previous findings of nonrandom distribution of SNPs across chromosome 2, suggest that the Plasmodium falciparum genome may be a mosaic with regard to genetic diversity, containing chromosomal regions that are highly polymorphic interspersed with regions that are much less polymorphic.

}, keywords = {*Genome, Protozoan, *Polymorphism, Single Nucleotide, Animals, DNA, Protozoan/analysis, Genes, Protozoan, Genetic Variation/*genetics, Microsatellite Repeats/*genetics, Plasmodium falciparum/*genetics, Protozoan Proteins/genetics}, isbn = {0378-1119 (Print)0378-1119 (Linking)}, author = {Volkman, S. K. and Lozovsky, E. and Barry, A. E. and Bedford, T. and Bethke, L. and Myrick, A. and Day, K. P. and Hartl, D. L. and Wirth, DF and Sawyer, S. A.} } @article {538826, title = {Malaria: a peek at the var variorum}, journal = {Trends Parasitol}, volume = {23}, number = {12}, year = {2007}, note = {

Chookajorn, ThanatCostanzo, Marna SHartl, Daniel LDeitsch, Kirk WengResearch Support, Non-U.S. Gov{\textquoteright}tReviewEngland2007/11/06 09:00Trends Parasitol. 2007 Dec;23(12):563-5. Epub 2007 Oct 30.

}, month = {Dec}, pages = {563-5}, abstract = {

Geneticists encountering the diversity of the malaria parasite{\textquoteright}s var gene family for the first time often complain that its complexity is a nightmare. A new article by Barry et al. presents the latest and most systematic attempt to date to decipher the var variorum. This important work, combined with other recent articles on var global variation such as that by Kraemer et al., suggests that only the tip of the var diversity iceberg is currently in view. In this article, we discuss these recent results and provide an overview of current understanding of var diversity.

}, keywords = {*Genes, Protozoan, *Genetic Variation, Animals, Evolution, Molecular, Humans, Malaria, Falciparum/*parasitology, Plasmodium falciparum/*genetics}, isbn = {1471-4922 (Print)1471-4922 (Linking)}, author = {Chookajorn, T. and Costanzo, M. S. and Hartl, D. L. and Deitsch, K. W.} } @article {539266, title = {Mud sticks: on the alleged falsification of Mendel{\textquoteright}s data}, journal = {Genetics}, volume = {175}, number = {3}, year = {2007}, note = {

Hartl, Daniel LFairbanks, Daniel JengHistorical Article2007/03/27 09:00Genetics. 2007 Mar;175(3):975-9.

}, month = {Mar}, pages = {975-9}, keywords = {Genetics/*history, History, 19th Century, History, 20th Century, Inheritance Patterns/*genetics, Research Design/standards, Scientific Misconduct/*history}, isbn = {0016-6731 (Print)0016-6731 (Linking)}, author = {Hartl, D. L. and Fairbanks, D. J.} } @article {538896, title = {Mutational reversions during adaptive protein evolution}, journal = {Mol Biol Evol}, volume = {24}, number = {8}, year = {2007}, note = {

DePristo, Mark AHartl, Daniel LWeinreich, Daniel MengResearch Support, Non-U.S. Gov{\textquoteright}tResearch Support, U.S. Gov{\textquoteright}t, Non-P.H.S.2007/06/09 09:00Mol Biol Evol. 2007 Aug;24(8):1608-10. Epub 2007 Jun 7.

}, month = {Aug}, pages = {1608-10}, abstract = {

Adaptation is often regarded as the sequential fixation of individually, intrinsically beneficial mutations. Contrary to this expectation, we find a surprisingly large number of evolutionary trajectories on which natural selection first favors a mutation, then favors its removal, and later still favors its ultimate restoration during the course of antibiotic resistance evolution. The existence of reversion trajectories implies that natural selection may not follow the most parsimonious path separating two alleles, even during adaptation. Altogether, this discovery highlights the unusual and potentially circuitous routes natural selection can follow during adaptation.

}, keywords = {*Evolution, Molecular, *Models, Genetic, *Mutation, *Selection, Genetic, Adaptation, Biological/*genetics, beta-Lactamases/*genetics, Humans}, isbn = {0737-4038 (Print)0737-4038 (Linking)}, author = {Depristo, M. A. and Hartl, D. L. and Weinreich, D.M.} } @article {538981, title = {Plasmodium falciparum: worldwide sequence diversity and evolution of the malaria vaccine candidate merozoite surface protein-2 (MSP-2)}, journal = {Exp Parasitol}, volume = {115}, number = {1}, year = {2007}, note = {

Ferreira, Marcelo UHartl, Daniel LengResearch Support, Non-U.S. Gov{\textquoteright}t2006/06/27 09:00Exp Parasitol. 2007 Jan;115(1):32-40. Epub 2006 Jun 21.

}, month = {Jan}, pages = {32-40}, abstract = {

We examined patterns and putative mechanisms of sequence diversification in the merozoite surface protein-2 (MSP-2) of Plasmodium falciparum, a major dimorphic malaria vaccine candidate antigen, by analyzing 448 msp-2 alleles from all continents. We describe several nucleotide replacements, insertion and deletion events, frameshift mutations, and proliferations of repeat units that generate the extraordinary diversity found in msp-2 alleles. We discuss the role of positive selection exerted by naturally acquired type- and variant-specific immunity in maintaining the observed levels of polymorphism and suggest that this is the most likely explanation for the significant excess of nonsynonymous nucleotide replacements found in dimorphic msp-2 domains. Hybrid sequences created by meiotic recombination between alleles of different dimorphic types were observed in few (3.1\%) isolates, mostly from Africa. We found no evidence for an extremely ancient origin of allelic dimorphism at the msp-2 locus, predating P. falciparum speciation, in contrast with recent findings for other surface malarial antigens.

}, keywords = {*Evolution, Molecular, *Genetic Variation, Alleles, Amino Acid Sequence, Animals, Antigens, Protozoan/*genetics/immunology, Base Sequence, DNA, Protozoan/chemistry, Malaria Vaccines/*genetics, Molecular Sequence Data, Plasmodium falciparum/*genetics/immunology, Polymorphism, Genetic, Protozoan Proteins/*genetics/immunology, Recombination, Genetic, Repetitive Sequences, Nucleic Acid, Sequence Alignment}, isbn = {0014-4894 (Print)0014-4894 (Linking)}, author = {Ferreira, M. U. and Hartl, D. L.} } @article {538986, title = {Population structure and transmission dynamics of Plasmodium vivax in rural Amazonia}, journal = {J Infect Dis}, volume = {195}, number = {8}, year = {2007}, note = {

Ferreira, Marcelo UKarunaweera, Nadira Dda Silva-Nunes, Monicada Silva, Natal SWirth, Dyann FHartl, Daniel LengR01 GM061351/GM/NIGMS NIH HHS/Research Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov{\textquoteright}t2007/03/16 09:00J Infect Dis. 2007 Apr 15;195(8):1218-26. Epub 2007 Mar 6.

}, month = {Apr 15}, pages = {1218-26}, abstract = {

Understanding the genetic structure of malaria parasites is essential to predict how fast some phenotypes of interest originate and spread in populations. In the present study, we used highly polymorphic microsatellite markers to analyze 74 Plasmodium vivax isolates, which we collected in cross-sectional and longitudinal surveys performed in an area of low malaria endemicity in Brazilian Amazonia, and to explore the transmission dynamics of genetically diverse haplotypes or strains. P. vivax populations are more diverse and more frequently comprise multiple-clone infections than do sympatric Plasmodium falciparum isolates, but these features paradoxically coexist with high levels of inbreeding, leading to significant multilocus linkage disequilibrium. Moreover, the high rates of microsatellite haplotype replacement that we found during 15 months of follow-up most likely do not result from strong diversifying selection. We conclude that the small-area genetic diversity in P. vivax populations under low-level transmission is not severely constrained by the low rates of effective meiotic recombination, with clear public health implications.

}, keywords = {*Genetic Variation, Animals, Brazil/epidemiology, Cross-Sectional Studies, Haplotypes, Humans, Linkage Disequilibrium/genetics, Longitudinal Studies, Malaria, Vivax/epidemiology/*transmission, Microsatellite Repeats/*genetics, Plasmodium vivax/classification/*genetics/pathogenicity, Polymorphism, Genetic, Rural Population, Time Factors}, isbn = {0022-1899 (Print)0022-1899 (Linking)}, author = {Ferreira, M. U. and Karunaweera, N. D. and da Silva-Nunes, M. and da Silva, N. S. and Wirth, DF and Hartl, D. L.} } @article {538911, title = {A portrait of copy-number polymorphism in Drosophila melanogaster}, journal = {Proc Natl Acad Sci U S A}, volume = {104}, number = {50}, year = {2007}, note = {

Dopman, Erik BHartl, Daniel Leng1 F32 GM080090-01/GM/NIGMS NIH HHS/GM068465/GM/NIGMS NIH HHS/Research Support, N.I.H., Extramural2007/12/07 09:00Proc Natl Acad Sci U S A. 2007 Dec 11;104(50):19920-5. Epub 2007 Dec 4.

}, month = {Dec 11}, pages = {19920-5}, abstract = {

Thomas Hunt Morgan and colleagues identified variation in gene copy number in Drosophila in the 1920s and 1930s and linked such variation to phenotypic differences [Bridges CB (1936) Science 83:210]. Yet the extent of variation in the number of chromosomes, chromosomal regions, or gene copies, and the importance of this variation within species, remain poorly understood. Here, we focus on copy-number variation in Drosophila melanogaster. We characterize copy-number polymorphism (CNP) across genomic regions, and we contrast patterns to infer the evolutionary processes acting on this variation. Copy-number variation in D. melanogaster is nonrandomly distributed, presumably because of a mutational bias produced by tandem repeats or other mechanisms. Comparisons of coding and noncoding CNPs, however, reveal a strong effect of purifying selection in the removal of structural variation from functionally constrained regions. Most patterns of CNP in D. melanogaster suggest that negative selection and mutational biases are the primary agents responsible for shaping structural variation.

}, keywords = {Animals, Biological Evolution, Chromosomes/genetics, Drosophila melanogaster/*genetics, Gene Dosage/*genetics, Gene Expression Regulation, Genome, Insect/genetics, Mutation/genetics, Organ Specificity, Polymorphism, Genetic/*genetics, Selection, Genetic}, isbn = {1091-6490 (Electronic)0027-8424 (Linking)}, author = {Dopman, E. B. and Hartl, D. L.} } @article {540001, title = {Prevalence of positive selection among nearly neutral amino acid replacements in Drosophila}, journal = {Proc Natl Acad Sci U S A}, volume = {104}, number = {16}, year = {2007}, note = {

Sawyer, Stanley AParsch, JohnZhang, ZhiHartl, Daniel LengGM61351/GM/NIGMS NIH HHS/GM68465/GM/NIGMS NIH HHS/Comparative StudyResearch Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov{\textquoteright}tResearch Support, U.S. Gov{\textquoteright}t, Non-P.H.S.2007/04/06 09:00Proc Natl Acad Sci U S A. 2007 Apr 17;104(16):6504-10. Epub 2007 Apr 4.

}, month = {Apr 17}, pages = {6504-10}, abstract = {

We have estimated the selective effects of amino acid replacements in natural populations by comparing levels of polymorphism in 91 genes in African populations of Drosophila melanogaster with their divergence from Drosophila simulans. The genes include about equal numbers whose level of expression in adults is greater in males, greater in females, or approximately equal in the sexes. Markov chain Monte Carlo methods were used to sample key parameters in the stationary distribution of polymorphism and divergence in a model in which the selective effect of each nonsynonymous mutation is regarded as a random sample from some underlying normal distribution whose mean may differ from one gene to the next. Our analysis suggests that approximately 95\% of all nonsynonymous mutations that could contribute to polymorphism or divergence are deleterious, and that the average proportion of deleterious amino acid polymorphisms in samples is approximately 70\%. On the other hand, approximately 95\% of fixed differences between species are positively selected, although the scaled selection coefficient (N(e)s) is very small. We estimate that approximately 46\% of amino acid replacements have N(e)s \< 2, approximately 84\% have N(e)s \< 4, and approximately 99\% have N(e)s \< 7. Although positive selection among amino acid differences between species seems pervasive, most of the selective effects could be regarded as nearly neutral. There are significant differences in selection between sex-biased and unbiased genes, which relate primarily to the mean of the distributions of mutational effects and the fraction of slightly deleterious and weakly beneficial mutations that are fixed.

}, keywords = {*Evolution, Molecular, *Selection, Genetic, Amino Acid Substitution/*genetics, Amino Acids, Neutral/*chemistry/*genetics, Animals, Drosophila melanogaster/chemistry/genetics, Drosophila Proteins/chemistry/*genetics, Female, Male, Markov Chains, Monte Carlo Method, Mutation, Polymorphism, Genetic, Species Specificity}, isbn = {0027-8424 (Print)0027-8424 (Linking)}, author = {Sawyer, S. A. and Parsch, J. and Zhang, Z. and Hartl, D. L.} } @article {540066, title = {A sex-ratio meiotic drive system in Drosophila simulans. I: an autosomal suppressor}, journal = {PLoS Biol}, volume = {5}, number = {11}, year = {2007}, note = {

Tao, YunMasly, John PAraripe, LucianaKe, YeyanHartl, Daniel LengGM51932/GM/NIGMS NIH HHS/GM65169/GM/NIGMS NIH HHS/Research Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov{\textquoteright}t2007/11/09 09:00PLoS Biol. 2007 Nov 6;5(11):e292.

}, month = {Nov 6}, pages = {e292}, abstract = {

Sex ratio distortion (sex-ratio for short) has been reported in numerous species such as Drosophila, where distortion can readily be detected in experimental crosses, but the molecular mechanisms remain elusive. Here we characterize an autosomal sex-ratio suppressor from D. simulans that we designate as not much yang (nmy, polytene chromosome position 87F3). Nmy suppresses an X-linked sex-ratio distorter, contains a pair of near-perfect inverted repeats of 345 bp, and evidently originated through retrotransposition from the distorter itself. The suppression is likely mediated by sequence homology between the suppressor and distorter. The strength of sex-ratio is greatly enhanced by lower temperature. This temperature sensitivity was used to assign the sex-ratio etiology to the maturation process of the Y-bearing sperm, a hypothesis corroborated by both light microscope observations and ultrastructural studies. It has long been suggested that an X-linked sex-ratio distorter can evolve by exploiting loopholes in the meiotic machinery for its own transmission advantage, which may be offset by other changes in the genome that control the selfish distorter. Data obtained in this study help to understand this evolutionary mechanism in molecular detail and provide insight regarding its evolutionary impact on genomic architecture and speciation.

}, keywords = {*Meiosis, *Sex Ratio, Animals, Drosophila/*genetics, Evolution, Molecular, Genes, Recessive, Molecular Sequence Data, Sex Chromosomes, Suppression, Genetic/*genetics}, isbn = {1545-7885 (Electronic)1544-9173 (Linking)}, author = {Tao, Y. and Masly, J. P. and Araripe, L. and Ke, Y. and Hartl, D. L.} } @article {540046, title = {A sex-ratio meiotic drive system in Drosophila simulans. II: an X-linked distorter}, journal = {PLoS Biol}, volume = {5}, number = {11}, year = {2007}, note = {

Tao, YunAraripe, LucianaKingan, Sarah BKe, YeyanXiao, HailianHartl, Daniel LengGM65169/GM/NIGMS NIH HHS/Research Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov{\textquoteright}t2007/11/09 09:00PLoS Biol. 2007 Nov 6;5(11):e293.

}, month = {Nov 6}, pages = {e293}, abstract = {

The evolution of heteromorphic sex chromosomes creates a genetic condition favoring the invasion of sex-ratio meiotic drive elements, resulting in the biased transmission of one sex chromosome over the other, in violation of Mendel{\textquoteright}s first law. The molecular mechanisms of sex-ratio meiotic drive may therefore help us to understand the evolutionary forces shaping the meiotic behavior of the sex chromosomes. Here we characterize a sex-ratio distorter on the X chromosome (Dox) in Drosophila simulans by genetic and molecular means. Intriguingly, Dox has very limited coding capacity. It evolved from another X-linked gene, which also evolved de nova. Through retrotransposition, Dox also gave rise to an autosomal suppressor, not much yang (Nmy). An RNA interference mechanism seems to be involved in the suppression of the Dox distorter by the Nmy suppressor. Double mutant males of the genotype dox; nmy are normal for both sex-ratio and spermatogenesis. We postulate that recurrent bouts of sex-ratio meiotic drive and its subsequent suppression might underlie several common features observed in the heterogametic sex, including meiotic sex chromosome inactivation and achiasmy.

}, keywords = {*Meiosis, *Sex Ratio, Amino Acid Sequence, Animals, Base Sequence, Chromosome Mapping, Drosophila Proteins/genetics, Drosophila/*genetics, Evolution, Molecular, Female, Genes, Suppressor, Male, Models, Genetic, Molecular Sequence Data, Phylogeny, RNA Interference, X Chromosome/*genetics, Y Chromosome/genetics}, isbn = {1545-7885 (Electronic)1544-9173 (Linking)}, author = {Tao, Y. and Araripe, L. and Kingan, SB and Ke, Y. and Xiao, H. and Hartl, D. L.} } @article {539466, title = {Systems-level analysis and evolution of the phototransduction network in Drosophila}, journal = {Proc Natl Acad Sci U S A}, volume = {104}, number = {9}, year = {2007}, note = {

Landry, Christian RCastillo-Davis, Cristian IOgura, AtsushiLiu, Jun SHartl, Daniel LengGM068465/GM/NIGMS NIH HHS/Comparative StudyResearch Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov{\textquoteright}t2007/03/16 09:00Proc Natl Acad Sci U S A. 2007 Feb 27;104(9):3283-8. Epub 2007 Feb 20.

}, month = {Feb 27}, pages = {3283-8}, abstract = {

Networks of interacting genes are responsible for generating life{\textquoteright}s complexity and for mediating how organisms respond to their environment. Thus, a basic understanding of genetic variation in gene networks in natural populations is important for elucidating how changes at the genetic level map to higher levels of biological organization. Here, using the well-characterized phototransduction network in Drosophila, we analyze variation in gene expression within and between two closely related species, Drosophila melanogaster and Drosophila simulans, under different environmental conditions. Gene expression levels in the pathway are largely conserved between these two sibling species. For most genes in the network, differences in level of gene expression between species are correlated with degree of polymorphism within species. However, one gene encoding the light-induced ion channel TRPL (transient receptor potential-like) shows an excess of expression divergence relative to polymorphism, suggesting a possible role for natural selection in shaping this expression difference between species. Finally, this difference in TRPL expression likely has significant functional consequences, because it is known that a high level of rhabdomeral TRPL leads to increased sensitivity to dim background light and an increased response to a wider range of light intensities. These results provide a preliminary quantification of variation and divergence of gene expression between species in a known gene network and provide a foundation for a system-level understanding of functional and evolutionary change.

}, keywords = {*Environment, *Evolution, Molecular, *Gene Expression Regulation, *Polymorphism, Genetic, Analysis of Variance, Animals, DNA Primers, Drosophila Proteins/genetics/metabolism, Drosophila/*genetics/physiology, Gene Expression Profiling, Gene Regulatory Networks/*genetics, Reverse Transcriptase Polymerase Chain Reaction, Sequence Analysis, DNA, Species Specificity, Transient Receptor Potential Channels/genetics/metabolism, Vision, Ocular/*genetics/physiology}, isbn = {0027-8424 (Print)0027-8424 (Linking)}, author = {Landry, C. R. and Castillo-Davis, C. I. and Ogura, A. and Liu, J. S. and Hartl, D. L.} } @article {538906, title = {On the abundance, amino acid composition, and evolutionary dynamics of low-complexity regions in proteins}, journal = {Gene}, volume = {378}, year = {2006}, note = {

DePristo, Mark AZilversmit, Martine MHartl, Daniel LengResearch Support, Non-U.S. Gov{\textquoteright}tNetherlands2006/06/30 09:00Gene. 2006 Aug 15;378:19-30. Epub 2006 May 11.

}, month = {Aug 15}, pages = {19-30}, abstract = {

Protein sequences frequently contain regions composed of a reduced number of amino acids. Despite their presence in about half of all proteins and their unusual prevalence in the malaria parasite Plasmodium falciparum, the function and evolution of such low-complexity regions (LCRs) remain unclear. Here we show that LCR abundance and amino acid composition depend largely, but not exclusively, on genomic A+T content and obey power-law growth dynamics. Further, our results indicate that LCRs are analogous to microsatellites in that DNA replication slippage and unequal crossover recombination are important molecular mechanisms for LCR expansion. We support this hypothesis by demonstrating that the size of LCR insertions/deletions among orthologous genes depends upon length. Moreover, we show that LCRs enable intra-exonic recombination in a key family of cell-surface antigens in P. falciparum and thus likely facilitate the generation of antigenic diversity. We conclude with a mechanistic model for LCR evolution that links the pattern of LCRs within P. falciparum to its high genomic A+T content and recombination rate.

}, keywords = {Amino Acids/analysis, Animals, Antigenic Variation, Antigens, Protozoan/chemistry/genetics, DNA, Protozoan/genetics, Evolution, Molecular, Genome, Protozoan, Microsatellite Repeats, Plasmodium falciparum/*chemistry/*genetics/immunology, Protozoan Proteins/*chemistry/*genetics/immunology, Recombination, Genetic}, isbn = {0378-1119 (Print)0378-1119 (Linking)}, author = {Depristo, M. A. and Zilversmit, M. M. and Hartl, D. L.} } @article {540156, title = {Darwinian evolution can follow only very few mutational paths to fitter proteins}, journal = {Science}, volume = {312}, number = {5770}, year = {2006}, note = {

Weinreich, Daniel MDelaney, Nigel FDepristo, Mark AHartl, Daniel LengResearch Support, Non-U.S. Gov{\textquoteright}tResearch Support, U.S. Gov{\textquoteright}t, Non-P.H.S.New York, N.Y.2006/04/08 09:00Science. 2006 Apr 7;312(5770):111-4.

}, month = {Apr 7}, pages = {111-4}, abstract = {

Five point mutations in a particular beta-lactamase allele jointly increase bacterial resistance to a clinically important antibiotic by a factor of approximately 100,000. In principle, evolution to this high-resistance beta-lactamase might follow any of the 120 mutational trajectories linking these alleles. However, we demonstrate that 102 trajectories are inaccessible to Darwinian selection and that many of the remaining trajectories have negligible probabilities of realization, because four of these five mutations fail to increase drug resistance in some combinations. Pervasive biophysical pleiotropy within the beta-lactamase seems to be responsible, and because such pleiotropy appears to be a general property of missense mutations, we conclude that much protein evolution will be similarly constrained. This implies that the protein tape of life may be largely reproducible and even predictable.

}, keywords = {*Drug Resistance, Bacterial, *Evolution, Molecular, *Mutation, Alleles, Anti-Bacterial Agents/pharmacology, beta-Lactamases/*genetics/metabolism, Cefotaxime/metabolism/*pharmacology, Enzyme Stability, Epistasis, Genetic, Escherichia coli/*drug effects/enzymology/genetics, Models, Genetic, Mutation, Missense, Point Mutation, Probability, Selection, Genetic}, isbn = {1095-9203 (Electronic)0036-8075 (Linking)}, author = {Weinreich, D.M. and Delaney, N. F. and Depristo, M. A. and Hartl, D. L.} } @article {538586, title = {Duplication, gene conversion, and genetic diversity in the species-specific acyl-CoA synthetase gene family of Plasmodium falciparum}, journal = {Mol Biochem Parasitol}, volume = {150}, number = {1}, year = {2006}, note = {

Bethke, Lara LZilversmit, MartineNielsen, KaareDaily, JohannaVolkman, Sarah KNdiaye, DaoudaLozovsky, Elena RHartl, Daniel LWirth, Dyann FengR01 AI058515/AI/NIAID NIH HHS/R01-GM061351/GM/NIGMS NIH HHS/Wellcome Trust/United KingdomResearch Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov{\textquoteright}tNetherlands2006/07/25 09:00Mol Biochem Parasitol. 2006 Nov;150(1):10-24. Epub 2006 Jul 10.

}, month = {Nov}, pages = {10-24}, abstract = {

While genes encoding antigens and other highly polymorphic proteins are commonly found in subtelomeres, it is unusual to find a small family of housekeeping genes in these regions. We found that in the species Plasmodium falciparum only, a non-subtelomeric acyl-CoA synthetase (ACS) gene has expanded into a family of duplicated genes mainly located in the subtelomeres of the genome. We identified the putative parent of the duplicated family by analysis of synteny and phylogeny relative to other Plasmodium ACS genes. All ten ACS paralogs are transcribed in erythrocytic stages of laboratory and field isolates. We identified and confirmed a recent double gene conversion event involving ACS genes on three different chromosomes of isolate 3D7, resulting in the creation of a new hybrid gene. Southern hybridization analysis of geographically diverse P. falciparum isolates provides evidence for the strikingly global conservation of the ACS gene family, but also for some chromosomal events, including deletion and recombination, involving the duplicated paralogs. We found a dramatically higher rate of non-synonymous substitutions per non-synonymous site than synonymous substitutions per synonymous site in the closely related ACS paralogs we sequenced, suggesting that these genes are under a form of selection that favors change in the state of the protein. We also found that the gene encoding acyl-CoA binding protein has expanded and diversified in P. falciparum. We have described a new class of subtelomeric gene family with a unique capacity for diversity in P. falciparum.

}, keywords = {Animals, Base Sequence, Blotting, Southern, Coenzyme A Ligases/*genetics, Erythrocytes/parasitology, Gene Conversion, Gene Duplication, Gene Expression Profiling, Genetic Variation, Malaria, Falciparum/genetics/parasitology, Models, Molecular, Molecular Sequence Data, Phylogeny, Plasmodium falciparum/classification/enzymology/*genetics/isolation \&, Plasmodium/genetics/isolation \& purification, Polymorphism, Single Nucleotide, Protein Conformation, Pseudogenes, purification, Species Specificity, Telomere/genetics}, isbn = {0166-6851 (Print)0166-6851 (Linking)}, author = {Bethke, L. L. and Zilversmit, M. and Nielsen, K. and Daily, J. and Volkman, S. K. and Ndiaye, D. and Lozovsky, E. R. and Hartl, D. L. and Wirth, DF} } @article {539486, title = {Ecological and evolutionary genomics of Saccharomyces cerevisiae}, journal = {Mol Ecol}, volume = {15}, number = {3}, year = {2006}, note = {

Landry, Christian RTownsend, Jeffrey PHartl, Daniel LCavalieri, DuccioengResearch Support, Non-U.S. Gov{\textquoteright}tReviewEngland2006/02/28 09:00Mol Ecol. 2006 Mar;15(3):575-91.

}, month = {Mar}, pages = {575-91}, abstract = {

Saccharomyces cerevisiae, the budding yeast, is the most thoroughly studied eukaryote at the cellular, molecular, and genetic levels. Yet, until recently, we knew very little about its ecology or population and evolutionary genetics. In recent years, it has been recognized that S. cerevisiae occupies numerous habitats and that populations harbour important genetic variation. There is therefore an increasing interest in understanding the evolutionary forces acting on the yeast genome. Several researchers have used the tools of functional genomics to study natural isolates of this unicellular fungus. Here, we review some of these studies, and show not only that budding yeast is a prime model system to address fundamental molecular and cellular biology questions, but also that it is becoming a powerful model species for ecological and evolutionary genomics studies as well.

}, keywords = {Ecology, Evolution, Molecular, Gene Expression Regulation, Fungal, Genetics, Population, Genome, Fungal, Genomics, Saccharomyces cerevisiae/*genetics}, isbn = {0962-1083 (Print)0962-1083 (Linking)}, author = {Landry, C. R. and Townsend, J. P. and Hartl, D. L. and Cavalieri, D.} } @article {539891, title = {The evolution of the novel Sdic gene cluster in Drosophila melanogaster}, journal = {Gene}, volume = {376}, number = {2}, year = {2006}, note = {

Ponce, RitaHartl, Daniel LengComparative StudyResearch Support, Non-U.S. Gov{\textquoteright}tNetherlands2006/06/13 09:00Gene. 2006 Jul 19;376(2):174-83. Epub 2006 Jun 12.

}, month = {Jul 19}, pages = {174-83}, abstract = {

The origin of new genes and of new functions for existing genes are fundamental processes in molecular evolution. Sdic is a newly evolved gene that arose recently in the D. melanogaster lineage. The gene encodes a novel sperm motility protein. It is a chimeric gene formed by duplication of two other genes followed by multiple deletions and other sequence rearrangements. The Sdic gene exists in several copies in the X chromosome, and is presumed to have undergone several duplications to form a tandemly arrayed gene cluster. Given the very recent origin of the gene and the gene cluster, the analysis of the composition of this gene cluster represents an excellent opportunity to study the origin and evolution of new gene functions and the fate of gene duplications. We have analyzed the nucleotide sequence of this region and reconstructed the evolutionary history of this gene cluster. We found that the cluster is composed by four tandem copies of Sdic; these duplicates are very similar but can be distinguished by the unique pattern of insertions, deletions, and point mutations in each copy. The oldest gene copy in the array has a 3{\textquoteright} exon that has undergone accelerated diversification, and also shows divergent regulatory sequences. Moreover, there is evidence that this might be the only gene copy in the tandem array that is transcribed at a significant level, expressing a novel sperm-specific protein. There is also a retrotransposon located at the 3{\textquoteright} end of each Sdic gene copy. We argue that this gene cluster was formed in the last two million years by at least three tandem duplications and one retrotransposition event.

}, keywords = {*Evolution, Molecular, *Genes, Insect, *Multigene Family, 3{\textquoteright} Untranslated Regions, Amino Acid Motifs, Amino Acid Sequence, Animals, Axonemal Dyneins, Base Sequence, DNA, Intergenic/chemistry, Drosophila melanogaster/*genetics, Drosophila Proteins/chemistry/*genetics, Dyneins/chemistry/*genetics, Exons, Gene Deletion, Gene Dosage, Gene Duplication, Gene Rearrangement, Genes, X-Linked, Genetic Variation, Molecular Sequence Data, Mutagenesis, Insertional, Phylogeny, Point Mutation, Promoter Regions, Genetic, Protein Structure, Tertiary, Regulatory Sequences, Nucleic Acid, Retroelements, Sequence Homology, Amino Acid, Transcription, Genetic}, isbn = {0378-1119 (Print)0378-1119 (Linking)}, author = {Ponce, R. and Hartl, D. L.} } @article {539481, title = {Genome-wide scan reveals that genetic variation for transcriptional plasticity in yeast is biased towards multi-copy and dispensable genes}, journal = {Gene}, volume = {366}, number = {2}, year = {2006}, note = {

Landry, Christian ROh, JuliaHartl, Daniel LCavalieri, DuccioengResearch Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov{\textquoteright}tNetherlands2006/01/24 09:00Gene. 2006 Feb 1;366(2):343-51. Epub 2006 Jan 20.

}, month = {Feb 1}, pages = {343-51}, abstract = {

One of the most important aspects of the evolution of development and physiology is the interplay between gene expression and the environment, by which traits become altered in response to environmental triggers. This feature is known as phenotypic plasticity. When different genotypes show different levels of plasticity for a trait, then they show genotype-by-environment interaction, or GEI. It is now clear that gene expression plays an important role in organismic-level phenotypic plasticity, but we know very little about whether gene expression itself is subject to genetic variation for phenotypic plasticity (GEI). Given that gene regulation is likely to have evolved to respond to environmental changes, it is of central importance to understand how environmental and genetic variation interact to produce variation in gene expression. Here we investigate genetic variation for phenotypic plasticity in the yeast transcriptome for the whole genome. Six strains of Saccharomyces cerevisiae were grown in four different environments representing a continuum of rich and poor natural conditions. Using DNA-microarray data and an ANOVA analysis with a stringent criterion of significance, we found significant genetic variation for transcriptional plasticity (GEI) among strains for approximately 5\% of the genes in the genome. There are about twice as many genes that show genetic variation for phenotypic plasticity as show genetic variation in transcription level independent of the environment. We also found that genes with genetic variation for plasticity were less likely to be essential and were significantly biased towards genes that have paralogs.

}, keywords = {*Genetic Variation, Adaptation, Physiological/*physiology, Biological Evolution, Environment, Gene Expression Regulation, Fungal/*physiology, Genome, Fungal/*physiology, Saccharomyces cerevisiae/*physiology, Transcription, Genetic/*physiology}, isbn = {0378-1119 (Print)0378-1119 (Linking)}, author = {Landry, C. R. and Oh, J. and Hartl, D. L. and Cavalieri, D.} } @article {538836, title = {Position-specific polymorphism of Plasmodium falciparum Stuttering motif in a PHISTc PFI1780w}, journal = {Exp Parasitol}, volume = {114}, number = {2}, year = {2006}, note = {

Chookajorn, ThanatHartl, Daniel LengResearch Support, Non-U.S. Gov{\textquoteright}t2006/05/06 09:00Exp Parasitol. 2006 Oct;114(2):126-8. Epub 2006 May 3.

}, month = {Oct}, pages = {126-8}, abstract = {

Several genes of Plasmodium falciparum are positively selected due to the pressure from the host immune system. This is a pattern completely opposite to that found in most housekeeping genes, which have few synonymous mutations. The discrepancy is an important topic in Plasmodium biology. We searched for unique polymorphism patterns in P. falciparum and identified a repetitive Stuttering motif in PFI1780w which was recently grouped as a gene in the PHIST family. The repeat has a position-specific polymorphism pattern in the otherwise highly conserved gene. Its mutations are limited to only one small region, and they are not consistent with replication slippage or gene conversion commonly found in low complexity regions. The repeat variation was analyzed in different strains of P. falciparum. The PFI1780w Stuttering motif can be a model to study gene diversification and used as a tool for strain typing.

}, keywords = {*Polymorphism, Genetic, Amino Acid Sequence, Animals, Antigens, Protozoan/chemistry/*genetics, Antigens, Surface/chemistry/genetics, Base Sequence, Exons/genetics, Membrane Proteins/chemistry/genetics, Molecular Sequence Data, Plasmodium falciparum/chemistry/*genetics/immunology, Protozoan Proteins/chemistry/*genetics, Sequence Analysis}, isbn = {0014-4894 (Print)0014-4894 (Linking)}, author = {Chookajorn, T. and Hartl, D. L.} } @article {538551, title = {Variable SNP density in aspartyl-protease genes of the malaria parasite Plasmodium falciparum}, journal = {Gene}, volume = {376}, number = {2}, year = {2006}, note = {

Barry, Alyssa ELeliwa-Sytek, AleksandraMan, KittyKasper, Jacob MHartl, Daniel LDay, Karen Peng2 R01 GM061351/GM/NIGMS NIH HHS/Wellcome Trust/United KingdomComparative StudyResearch Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov{\textquoteright}tNetherlands2006/06/21 09:00Gene. 2006 Jul 19;376(2):163-73. Epub 2006 Apr 5.

}, month = {Jul 19}, pages = {163-73}, abstract = {

An analysis of the diversity of the aspartyl proteases of Plasmodium falciparum, known as plasmepsins (PMs), was completed in view of their possible role as drug targets. DNA sequence polymorphisms were identified in nine pm genes including their non-coding (introns and 5{\textquoteright} flanking) sequences. All genes contained at least one single nucleotide polymorphism (SNP). Extensive microsatellite diversity was observed predominantly in non-coding sequences. All but one non-synonymous polymorphism (a conservative substitution) were mapped to the surface of the predicted protein, contradicting a possible role in enzymatic activity. The distribution of SNPs was found to be non-random among pm genes, with pm6 and pm10 having significantly higher SNP densities, suggesting they were under selection. For pm6 the majority of the SNPs were in introns and some of these may contribute to splice site variation. SNPs were found at a high density in both the coding and non-coding sequences of pm10. Recombination was important in generating additional diversity at this locus. Although direct selection for pm10 mutations could not be ruled out, the presence of balancing selection and a high density of SNPs in non-coding sequence led us to propose that another gene under selection may be influencing the diversity in the region. By sequencing short DNA tags in a 200 kb region flanking pm10 we show that a cluster of antigen genes, known to be under diversifying selection, may contribute to the observed diversity. We discuss the importance of diversity and local selection effects when choosing drug targets for intervention strategies.

}, keywords = {*Genes, Protozoan, *Polymorphism, Single Nucleotide, Animals, Aspartic Acid Endopeptidases/*genetics, Base Sequence, Chromosome Mapping, Chromosomes, DNA, Protozoan/genetics, Evolution, Molecular, Gene Frequency, Genetic Variation, Introns, Microsatellite Repeats, Molecular Sequence Data, Mutation, Plasmodium falciparum/*enzymology/*genetics/isolation \& purification, Recombination, Genetic, Selection, Genetic, Sequence Analysis, DNA}, isbn = {0378-1119 (Print)0378-1119 (Linking)}, author = {Barry, A. E. and Leliwa-Sytek, A. and Man, K. and Kasper, J. M. and Hartl, D. L. and Day, K. P.} } @article {539956, title = {Very little intron loss/gain in Plasmodium: intron loss/gain mutation rates and intron number}, journal = {Genome Res}, volume = {16}, number = {6}, year = {2006}, note = {

Roy, Scott WilliamHartl, Daniel LengComparative StudyResearch Support, Non-U.S. Gov{\textquoteright}t2006/05/17 09:00Genome Res. 2006 Jun;16(6):750-6. Epub 2006 May 15.

}, month = {Jun}, pages = {750-6}, abstract = {

We compared intron positions in conserved regions of 3479 orthologous gene pairs from Plasmodium falciparum and Plasmodium yoelii, which likely diverged \>or=100 million years ago (Mya). Only 27 out of 2212 positions were specific to one of the two species. Intron presence in related species shows that at least 19 and possibly 26 of the changes are due to intron loss, depending on phylogeny. The implied intron loss and gain rates are much lower than previously estimated for nematodes, arthropods, fungi, and plants, and are comparable only with the rates in vertebrates. That all observed changes were exact, occurring without loss or gain of flanking coding sequence, suggests intron loss via an mRNA intermediate, as does a nonsignificant trend toward loss of introns at adjacent positions. Many of the intron changes occurred in genes encoding proteins involved in nucleic acid-related processes, as previously found for intron gains in nematodes. Two changes occurred in the chloroquine resistance transporter, suggesting a role for positive selection in intron loss in Plasmodium. The dearth of intron loss and gain could be explained by the lack of known transposable elements in Plasmodium, since transposable elements and/or reverse transcriptase are thought to be necessary for both processes. The observed pattern suggests that the availability of stochastic intron loss and gain mutations can be a major determinant of changes in intron number.

}, keywords = {*Mutation, Alternative Splicing/genetics, Amino Acid Sequence, Animals, Databases, Genetic, DNA Transposable Elements, Evolution, Molecular, Expressed Sequence Tags, Genes, Protozoan, Introns/*genetics, Membrane Proteins/genetics, Membrane Transport Proteins, Molecular Sequence Data, Plasmodium falciparum/*genetics, Plasmodium yoelii/*genetics, Protozoan Proteins}, isbn = {1088-9051 (Print)1088-9051 (Linking)}, author = {Roy, S. W. and Hartl, D. L.} } @article {539491, title = {Compensatory cis-trans evolution and the dysregulation of gene expression in interspecific hybrids of Drosophila}, journal = {Genetics}, volume = {171}, number = {4}, year = {2005}, note = {

Landry, Christian RWittkopp, Patricia JTaubes, Clifford HRanz, Jose MClark, Andrew GHartl, Daniel LengGM 60035/GM/NIGMS NIH HHS/GM 68465/GM/NIGMS NIH HHS/R01 AI 064950/AI/NIAID NIH HHS/Comparative StudyResearch Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov{\textquoteright}t2005/09/07 09:00Genetics. 2005 Dec;171(4):1813-22. Epub 2005 Sep 2.

}, month = {Dec}, pages = {1813-22}, abstract = {

Hybrids between species are often characterized by novel gene-expression patterns. A recent study on allele-specific gene expression in hybrids between species of Drosophila revealed cases in which cis- and trans-regulatory elements within species had coevolved in such a way that changes in cis-regulatory elements are compensated by changes in trans-regulatory elements. We hypothesized that such coevolution should often lead to gene misexpression in the hybrid. To test this hypothesis, we estimated allele-specific expression and overall expression levels for 31 genes in D. melanogaster, D. simulans, and their F1 hybrid. We found that 13 genes with cis-trans compensatory evolution are in fact misexpressed in the hybrid. These represent candidate genes whose dysregulation might be the consequence of coevolution of cis- and trans-regulatory elements within species. Using a mathematical model for the regulation of gene expression, we explored the conditions under which cis-trans compensatory evolution can lead to misexpression in interspecific hybrids.

}, keywords = {*Alleles, *Evolution, Molecular, *Gene Expression Regulation, *Hybridization, Genetic, *Models, Genetic, Animals, Drosophila/*genetics, Polymerase Chain Reaction, Regulatory Elements, Transcriptional/*genetics}, isbn = {0016-6731 (Print)0016-6731 (Linking)}, author = {Landry, C. R. and Wittkopp, P. J. and Taubes, C. H. and Ranz, J. M. and Clark, A. G. and Hartl, D. L.} } @article {539751, title = {Convergent loss of an anciently duplicated, functionally divergent RH2 opsin gene in the fugu and Tetraodon pufferfish lineages}, journal = {Gene}, volume = {350}, number = {2}, year = {2005}, note = {

Neafsey, Daniel EHartl, Daniel LengComparative StudyResearch Support, Non-U.S. Gov{\textquoteright}tResearch Support, U.S. Gov{\textquoteright}t, Non-P.H.S.Netherlands2005/04/12 09:00Gene. 2005 May 9;350(2):161-71. Epub 2005 Apr 7.

}, month = {May 9}, pages = {161-71}, abstract = {

We describe the complete opsin gene families from the sequenced fugu and Tetraodon pufferfish genomes. We report the convergent loss of function of an anciently duplicated, functionally divergent RH2 or "green-sensitive" opsin gene in both pufferfish lineages, designated RH2-2. In fugu, RH2-2 apparently ceased to function very recently following a transposon-induced deletion that truncated the N-terminal 115 amino acids from the translated protein. Although a lack of frameshift or nonsense mutations in the fugu RH2-2 pseudogene suggests that the gene was lost very recently in this lineage, we were unable to detect any evidence of a selective sweep associated with the fixation of the truncated allele from population data. Interspecific comparison of the remaining fugu RH2-2 coding sequence paradoxically indicates that the gene was under strong purifying selection until the truncation occurred.

}, keywords = {Amino Acid Sequence, Base Sequence, DNA/chemistry/genetics, Fish Proteins/genetics, Gene Duplication, Gene Expression, Genetic Variation, Molecular Sequence Data, Multigene Family/genetics, Phylogeny, Polymorphism, Genetic, Rod Opsins/*genetics, Sequence Alignment, Sequence Analysis, DNA, Sequence Homology, Amino Acid, Sequence Homology, Nucleic Acid, Species Specificity, Takifugu/*genetics, Tetraodontiformes/*genetics}, isbn = {0378-1119 (Print)0378-1119 (Linking)}, author = {Neafsey, D. E. and Hartl, D. L.} } @article {538596, title = {Evidence for maternally transmitted small interfering RNA in the repression of transposition in Drosophila virilis}, journal = {Proc Natl Acad Sci U S A}, volume = {102}, number = {44}, year = {2005}, note = {

Blumenstiel, Justin PHartl, Daniel LengGM068465/GM/NIGMS NIH HHS/GM60035/GM/NIGMS NIH HHS/Research Support, N.I.H., Extramural2005/10/26 09:00Proc Natl Acad Sci U S A. 2005 Nov 1;102(44):15965-70. Epub 2005 Oct 24.

}, month = {Nov 1}, pages = {15965-70}, abstract = {

Hybrid dysgenesis in Drosophila is a syndrome of gonadal atrophy, sterility, and male recombination, and it occurs in the progeny of crosses between males that harbor certain transposable elements (TEs) and females that lack them. Known examples of hybrid dysgenesis in Drosophila melanogaster result from mobilization of individual families of TEs, such as the P element, the I element, or hobo. An example of hybrid dysgenesis in Drosophila virilis is unique in that multiple, unrelated families of TEs become mobilized, but a TE designated Penelope appears to play a major role. In all known examples of hybrid dysgenesis, the paternal germ line transmits the TEs in an active state, whereas the female germ line maintains repression of the TEs. The mechanism of maternal maintenance of repression is not known. Recent evidence suggests that the molecular machinery of RNA interference may function as an important host defense against TEs. This protection is mediated by the action of endogenous small interfering RNAs (siRNAs) composed of dsRNA molecules of 21-25 nt that can target complementary transcripts for destruction. In this paper, we demonstrate that endogenous siRNA derived from the Penelope element is maternally loaded in embryos through the female germ line in D. virilis. We also present evidence that the maternal inheritance of these endogenous siRNAs may contribute to maternal repression of Penelope.

}, keywords = {*Inheritance Patterns, Animals, DNA Transposable Elements/*genetics, Drosophila/genetics, Female, Gene Expression Regulation, Germ Cells, Gonadal Dysgenesis/genetics, Male, RNA, Small Interfering/*genetics, X Chromosome}, isbn = {0027-8424 (Print)0027-8424 (Linking)}, author = {Blumenstiel, J. P. and Hartl, D. L.} } @article {539756, title = {Evolution of noncoding and silent coding sites in the Plasmodium falciparum and Plasmodium reichenowi genomes}, journal = {Mol Biol Evol}, volume = {22}, number = {7}, year = {2005}, note = {

Neafsey, Daniel EHartl, Daniel LBerriman, MattengGM61351/GM/NIGMS NIH HHS/Research Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov{\textquoteright}tResearch Support, U.S. Gov{\textquoteright}t, P.H.S.2005/04/29 09:00Mol Biol Evol. 2005 Jul;22(7):1621-6. Epub 2005 Apr 27.

}, month = {Jul}, pages = {1621-6}, abstract = {

We compared levels of sequence divergence between fourfold synonymous coding sites and noncoding sites from the intergenic and intronic regions of the Plasmodium falciparum and Plasmodium reichenowi genomes. We observed significant differences in the level of divergence between these classes of silent sites. Fourfold synonymous coding sites exhibited the highest level of sequence divergence, followed by introns, and then intergenic sequences. This pattern of relative divergence rates has been observed in primate genomes but was unexpected in Plasmodium due to a paucity of variation at silent sites in P. falciparum and the corollary hypothesis that silent sites in this genome may be subject to atypical selective constraints. Exclusion of hypermutable CpG dinucleotides reduces the divergence level of synonymous coding sites to that of intergenic sites but does not diminish the significantly higher divergence level of introns relative to intergenic sites. A greater than expected incidence of CpG dinucleotides in intergenic regions less than 500 bp from genes may indicate selective maintenance of regulatory motifs containing CpGs. Divergence rates of different classes of silent sites in these Plasmodium genomes are determined by a combination of mutational and selective pressures.

}, keywords = {*Conserved Sequence, *DNA, Intergenic, *Evolution, Molecular, *Phylogeny, Animals, Base Sequence, Genes, Insect, genome, Mutagenesis, Plasmodium falciparum/*genetics, Plasmodium/*genetics, Sequence Alignment}, isbn = {0737-4038 (Print)0737-4038 (Linking)}, author = {Neafsey, D. E. and Hartl, D. L. and Berriman, M.} } @article {539541, title = {Evolution of proteins and gene expression levels are coupled in Drosophila and are independently associated with mRNA abundance, protein length, and number of protein-protein interactions}, journal = {Mol Biol Evol}, volume = {22}, number = {5}, year = {2005}, note = {

Lemos, BernardoBettencourt, Brian RMeiklejohn, Colin DHartl, Daniel LengComparative StudyResearch Support, N.I.H., ExtramuralResearch Support, U.S. Gov{\textquoteright}t, P.H.S.2005/03/05 09:00Mol Biol Evol. 2005 May;22(5):1345-54. Epub 2005 Mar 2.

}, month = {May}, pages = {1345-54}, abstract = {

Organismic evolution requires that variation at distinct hierarchical levels and attributes be coherently integrated, often in the face of disparate environmental and genetic pressures. A central part of the evolutionary analysis of biological systems remains to decipher the causal connections between organism-wide (or genome-wide) attributes (e.g., mRNA abundance, protein length, codon bias, recombination rate, genomic position, mutation rate, etc) as well as their role-together with mutation, selection, and genetic drift-in shaping patterns of evolutionary variation in any of the attributes themselves. Here we combine genome-wide evolutionary analysis of protein and gene expression data to highlight fundamental relationships among genomic attributes and their associations with the evolution of both protein sequences and gene expression levels. Our results show that protein divergence is positively coupled with both gene expression polymorphism and divergence. We show moreover that although the number of protein-protein interactions in Drosophila is negatively associated with protein divergence as well as gene expression polymorphism and divergence, protein-protein interactions cannot account for the observed coupling between regulatory and structural evolution. Furthermore, we show that proteins with higher rates of amino acid substitutions tend to have larger sizes and tend to be expressed at lower mRNA abundances, whereas genes with higher levels of gene expression divergence and polymorphism tend to have shorter sizes and tend to be expressed at higher mRNA abundances. Finally, we show that protein length is negatively associated with both number of protein-protein interactions and mRNA abundance and that interacting proteins in Drosophila show similar amounts of divergence. We suggest that protein sequences and gene expression are subjected to similar evolutionary dynamics, possibly because of similarity in the fitness effect (i.e., strength of stabilizing selection) of disruptions in a gene{\textquoteright}s protein sequence or its mRNA expression. We conclude that, as more and better data accumulate, understanding the causal connections among biological traits and how they are integrated over time to constrain or promote structural and regulatory evolution may finally become possible.

}, keywords = {*Evolution, Molecular, *Gene Expression, *Genetic Variation, Animals, Drosophila Proteins/*genetics/metabolism, Drosophila/*genetics/metabolism, RNA, Messenger/*genetics/metabolism, Selection, Genetic}, isbn = {0737-4038 (Print)0737-4038 (Linking)}, author = {Lemos, B. and Bettencourt, B. R. and Meiklejohn, C. D. and Hartl, D. L.} } @article {539461, title = {The latest buzz in comparative genomics}, journal = {Genome Biol}, volume = {6}, number = {1}, year = {2005}, note = {

Kulathinal, Rob JHartl, Daniel LengComparative StudyReviewEngland2005/01/12 09:00Genome Biol. 2005;6(1):201. Epub 2005 Jan 4.

}, pages = {201}, abstract = {

A second species of fruit fly has just been added to the growing list of organisms with complete and annotated genome sequences. The publication of the Drosophila pseudoobscura sequence provides a snapshot of how genomes have changed over tens of millions of years and sets the stage for the analysis of more fly genomes.

}, keywords = {*Genome, Animals, Drosophila melanogaster/genetics, Drosophila/*classification/*genetics, Evolution, Molecular, Genomics/*trends}, isbn = {1465-6914 (Electronic)1465-6906 (Linking)}, author = {Kulathinal, R. J. and Hartl, D. L.} } @article {538901, title = {Missense meanderings in sequence space: a biophysical view of protein evolution}, journal = {Nat Rev Genet}, volume = {6}, number = {9}, year = {2005}, note = {

DePristo, Mark AWeinreich, Daniel MHartl, Daniel LengResearch Support, Non-U.S. Gov{\textquoteright}tResearch Support, U.S. Gov{\textquoteright}t, Non-P.H.S.ReviewEngland2005/08/03 09:00Nat Rev Genet. 2005 Sep;6(9):678-87.

}, month = {Sep}, pages = {678-87}, abstract = {

Proteins are finicky molecules; they are barely stable and are prone to aggregate, but they must function in a crowded environment that is full of degradative enzymes bent on their destruction. It is no surprise that many common diseases are due to missense mutations that affect protein stability and aggregation. Here we review the literature on biophysics as it relates to molecular evolution, focusing on how protein stability and aggregation affect organismal fitness. We then advance a biophysical model of protein evolution that helps us to understand phenomena that range from the dynamics of molecular adaptation to the clock-like rate of protein evolution.

}, keywords = {*Evolution, Molecular, *Models, Genetic, Adaptation, Biological/*genetics, Biophysical Phenomena, Biophysics, DNA/*genetics, Mutation, Missense/*genetics, Protein Conformation, protein folding, Proteins/*genetics/metabolism, Selection, Genetic}, isbn = {1471-0056 (Print)1471-0056 (Linking)}, author = {Depristo, M. A. and Weinreich, D.M. and Hartl, D. L.} } @article {539556, title = {Rates of divergence in gene expression profiles of primates, mice, and flies: stabilizing selection and variability among functional categories}, journal = {Evolution}, volume = {59}, number = {1}, year = {2005}, note = {

Lemos, BernardoMeiklejohn, Colin DCaceres, MarioHartl, Daniel LengComparative StudyResearch Support, U.S. Gov{\textquoteright}t, P.H.S.2005/03/29 09:00Evolution. 2005 Jan;59(1):126-37.

}, month = {Jan}, pages = {126-37}, abstract = {

The extent to which natural selection shapes phenotypic variation has long been a matter of debate among those studying organic evolution. We studied the patterns of gene expression polymorphism and divergence in several datasets that ranged from comparisons between two very closely related laboratory strains of mice to comparisons across a considerably longer time scale, such as between humans and chimpanzees, two species of mice, and two species of Drosophila. The results were analyzed and interpreted in view of neutral models of phenotypic evolution. Our analyses used a number of metrics to show that most mRNA levels are evolutionary stable, changing little across the range of taxonomic distances compared. This implies that, overall, widespread stabilizing selection on transcription levels has prevented greater evolutionary changes in mRNA levels. Nevertheless, the range of rates of divergence is large with highly significant differences in the rate and patterns of transcription divergence across functional classes defined on the basis of the gene ontology annotation (primates and mice datasets) or on the basis of the pattern of sex-biased gene expression (Drosophila). Moreover, rates of divergence of sex-biased genes in the contrast between Drosophila species show a distinct pattern from that observed in the contrast between populations of D. melanogaster. Hence, we discuss the time scale of the changes observed and its consequences for the relationship between variation in gene expression within and between species. Finally, we argue that differences in mRNA levels of the magnitudes observed herein could be explained by a remarkably small number of generations of directional selection.

}, keywords = {*Evolution, Molecular, *Genetic Variation, Animals, Brain, Drosophila melanogaster/*genetics, Gene Expression Profiling, Humans, Liver, Mice/*genetics, Oligonucleotide Array Sequence Analysis, Pan troglodytes/*genetics, Phenotype, RNA, Messenger/biosynthesis/genetics, Selection, Genetic}, isbn = {0014-3820 (Print)0014-3820 (Linking)}, author = {Lemos, B. and Meiklejohn, C. D. and Caceres, M. and Hartl, D. L.} } @article {538751, title = {Accelerated rates of intron gain/loss and protein evolution in duplicate genes in human and mouse malaria parasites}, journal = {Mol Biol Evol}, volume = {21}, number = {7}, year = {2004}, note = {

Castillo-Davis, Cristian IBedford, Trevor B CHartl, Daniel LengGM61351/GM/NIGMS NIH HHS/Research Support, Non-U.S. Gov{\textquoteright}tResearch Support, U.S. Gov{\textquoteright}t, P.H.S.2004/04/16 05:00Mol Biol Evol. 2004 Jul;21(7):1422-7. Epub 2004 Apr 14.

}, month = {Jul}, pages = {1422-7}, abstract = {

Very little is known about molecular evolution in the human malaria parasite Plasmodium falciparum. Given the potentially important role that introns play in directing transcription and the posttranscriptional control of gene expression, we compare rates of intron/gain loss and intronic substitution in P. falciparum and the rodent malaria P. y. yoelii in both orthologous and duplicate genes. Specifically, we test the hypothesis that intron gain/loss and protein evolution is accelerated in duplicate genes versus orthologous genes in both parasites using the genome sequence of both species. We find that duplicate genes in both P. falciparum and P. y. yoelii exhibit a dramatic acceleration of both intron gain/loss and protein evolution in comparison with orthologs, suggesting increased directional and/or relaxed selection in duplicate genes. Further, we find that rates of intron gain/loss and protein evolution are weakly coupled in orthologs but not paralogs, supporting the hypothesis that selection acts on genes as functionally integrated units after speciation but not necessarily after gene duplication. In contrast, we find that rates of nucleotide substitution do not differ significantly between intronic sites and synonymous sites among duplicate genes, implying that a large fraction of intronic sites in Plasmodium evolve under little or no selective constraint.

}, keywords = {*Evolution, Molecular, Animals, Genes, Duplicate/*genetics, Humans, Introns/*genetics, Malaria/parasitology, Mice, Plasmodium falciparum/*genetics, Plasmodium yoelii/*genetics, Protozoan Proteins/*genetics}, isbn = {0737-4038 (Print)0737-4038 (Linking)}, author = {Castillo-Davis, C. I. and Bedford, T. B. and Hartl, D. L.} } @article {539906, title = {Anomalies in the expression profile of interspecific hybrids of Drosophila melanogaster and Drosophila simulans}, journal = {Genome Res}, volume = {14}, number = {3}, year = {2004}, note = {

Ranz, Jose MNamgyal, KalsangGibson, GregHartl, Daniel LengResearch Support, Non-U.S. Gov{\textquoteright}tResearch Support, U.S. Gov{\textquoteright}t, P.H.S.2004/02/14 05:00Genome Res. 2004 Mar;14(3):373-9. Epub 2004 Feb 12.

}, month = {Mar}, pages = {373-9}, abstract = {

When females of Drosophila melanogaster and males of Drosophila simulans are mated, the male progeny are inviable, whereas the female progeny display manifold malformations and are sterile. These abnormalities result from genetic incompatibilities accumulated since the time the lineages of the species diverged, and may have their origin in aberrant gene transcription. Because compensatory changes within species may obscure differences at the regulatory level in conventional comparisons of the expression profile between species, we have compared the gene-expression profile of hybrid females with those of females of the parental species in order to identify regulatory incompatibilities. In the hybrid females, we find abnormal levels of messenger RNA for a large fraction of the Drosophila transcriptome. These include a gross underexpression of genes preferentially expressed in females, accompanying gonadal atrophy. The hybrid females also show significant overexpression of male-biased genes, which we attribute to incompatibilities in the regulatory mechanisms that normally act to control the expression of these genes in females. The net result of the multiple incompatibilities is that the gene-expression profiles of the parental females are more similar to each other than either is to that of the hybrid.

}, keywords = {*Crosses, Genetic, Animals, Breeding/methods, DNA, Complementary/classification/genetics, Drosophila melanogaster/embryology/*genetics, Drosophila/embryology/*genetics, Embryo, Nonmammalian/*abnormalities/chemistry/metabolism, Female, Gene Expression Profiling/*methods, Gene Expression Regulation, Developmental/genetics, Genes, Insect/genetics, Genes, Lethal/genetics, Hybridization, Genetic/*genetics, Male, Molecular Sequence Data, Oligonucleotide Array Sequence Analysis/*methods, Sex Factors}, isbn = {1088-9051 (Print)1088-9051 (Linking)}, author = {Ranz, J. M. and Namgyal, K. and Gibson, G. and Hartl, D. L.} } @article {538771, title = {cis-Regulatory and protein evolution in orthologous and duplicate genes}, journal = {Genome Res}, volume = {14}, number = {8}, year = {2004}, note = {

Castillo-Davis, Cristian IHartl, Daniel LAchaz, GuillaumeengComparative StudyResearch Support, Non-U.S. Gov{\textquoteright}t2004/07/17 05:00Genome Res. 2004 Aug;14(8):1530-6. Epub 2004 Jul 15.

}, month = {Aug}, pages = {1530-6}, abstract = {

The relationship between protein and regulatory sequence evolution is a central question in molecular evolution. It is currently not known to what extent changes in gene expression are coupled with the evolution of protein coding sequences, or whether these changes differ among orthologs (species homologs) and paralogs (duplicate genes). Here, we develop a method to measure the extent of functionally relevant cis-regulatory sequence change in homologous genes, and validate it using microarray data and experimentally verified regulatory elements in different eukaryotic species. By comparing the genomes of Caenorhabditis elegans and C. briggsae, we found that protein and regulatory evolution is weakly coupled in orthologs but not paralogs, suggesting that selective pressure on gene expression and protein evolution is quite similar and persists for a significant amount of time following speciation but not gene duplication. Additionally, duplicates of both species exhibit a dramatic acceleration of both regulatory and protein evolution compared to orthologs, suggesting increased directional selection and/or relaxed selection on both gene expression patterns and protein function in duplicate genes.

}, keywords = {*Evolution, Molecular, *Genes, Duplicate, *Genome, Bacterial, *Regulatory Sequences, Nucleic Acid, Animals, Caenorhabditis elegans Proteins/genetics, Caenorhabditis elegans/*genetics, Caenorhabditis/classification/*genetics, Chromosome Mapping, DNA, Bacterial/*genetics, Statistics as Topic}, isbn = {1088-9051 (Print)1088-9051 (Linking)}, author = {Castillo-Davis, C. I. and Hartl, D. L. and Achaz, G.} } @article {539456, title = {Compensated deleterious mutations in insect genomes}, journal = {Science}, volume = {306}, number = {5701}, year = {2004}, note = {

Kulathinal, Rob JBettencourt, Brian RHartl, Daniel LengGM068465/GM/NIGMS NIH HHS/P41-HG00739/HG/NHGRI NIH HHS/Research Support, Non-U.S. Gov{\textquoteright}tResearch Support, U.S. Gov{\textquoteright}t, P.H.S.New York, N.Y.2004/10/23 09:00Science. 2004 Nov 26;306(5701):1553-4. Epub 2004 Oct 21.

}, month = {Nov 26}, pages = {1553-4}, abstract = {

Relatively little is known about the importance of amino acid interactions in protein and phenotypic evolution. Here we examine whether mutations that are pathogenic in Drosophila melanogaster become fixed via epistasis in other Dipteran genomes. Overall divergence at pathogenic amino acid sites is reduced. However, approximately 10\% of the substitutions at these sites carry the exact same pathogenic amino acid found in D. melanogaster mutants. Hence compensatory mutation(s) must have evolved. Surprisingly, the fraction 10\% is not affected by phylogenetic distance. These results support a selection-driven process that allows compensated amino acid substitutions to become rapidly fixed in taxa with large populations.

}, keywords = {*Evolution, Molecular, *Genome, *Mutation, Amino Acid Sequence, Amino Acid Substitution, Animals, Anopheles gambiae/*genetics, Codon, Nonsense, Drosophila melanogaster/*genetics, Drosophila/*genetics, Epistasis, Genetic, Genes, Insect, Insect Proteins/chemistry/*genetics, Molecular Sequence Data, Mutation, Missense, Phenotype, Phylogeny, Selection, Genetic, Sequence Alignment}, isbn = {1095-9203 (Electronic)0036-8075 (Linking)}, author = {Kulathinal, R. J. and Bettencourt, B. R. and Hartl, D. L.} } @article {539746, title = {Different regulatory mechanisms underlie similar transposable element profiles in pufferfish and fruitflies}, journal = {Mol Biol Evol}, volume = {21}, number = {12}, year = {2004}, note = {

Neafsey, Daniel EBlumenstiel, Justin PHartl, Daniel LengComparative StudyResearch Support, Non-U.S. Gov{\textquoteright}tResearch Support, U.S. Gov{\textquoteright}t, Non-P.H.S.2004/09/03 05:00Mol Biol Evol. 2004 Dec;21(12):2310-8. Epub 2004 Sep 1.

}, month = {Dec}, pages = {2310-8}, abstract = {

Comparative analysis of recently sequenced eukaryotic genomes has uncovered extensive variation in transposable element (TE) abundance, diversity, and distribution. The TE profile in the sequenced pufferfish genomes is more similar to that of Drosophila melanogaster than to human or mouse, in that pufferfish TEs exhibit low overall abundance, high family diversity, and localization in the heterochromatin. It has been suggested that selection against the deleterious effects of ectopic recombination between TEs has structured the TE profile in Drosophila and pufferfish but not in humans. We test this hypothesis by measuring the sample frequency of 48 euchromatic TE insertions in the genome of the green spotted pufferfish (Tetraodon nigroviridis). We estimate the strength of selection acting on recent insertions by analyzing the site frequency spectrum using a maximum-likelihood approach. We show that in contrast to Drosophila, euchromatic TE insertions in Tetraodon are selectively neutral and that the low copy number and compartmentalized distribution of TEs in the Tetraodon genome must be caused by regulation by means other than purifying selection acting on recent insertions. Inference of regulatory processes governing TE profiles should take into account factors such as effective population size, incidence of inbreeding/outcrossing, and other species-specific traits.

}, keywords = {*Evolution, Molecular, *Genetics, Population, *Selection, Genetic, Animals, Base Sequence, Computational Biology, Databases, Nucleic Acid, DNA Primers, DNA Transposable Elements/*genetics, DNA, Mitochondrial/genetics, Drosophila/*genetics, Likelihood Functions, Molecular Sequence Data, Sequence Analysis, DNA, Tetraodontiformes/*genetics}, isbn = {0737-4038 (Print)0737-4038 (Linking)}, author = {Neafsey, D. E. and Blumenstiel, J. P. and Hartl, D. L.} } @article {538776, title = {The functional genomic distribution of protein divergence in two animal phyla: coevolution, genomic conflict, and constraint}, journal = {Genome Res}, volume = {14}, number = {5}, year = {2004}, note = {

Castillo-Davis, Cristian IKondrashov, Fyodor AHartl, Daniel LKulathinal, Rob JengComparative StudyResearch Support, Non-U.S. Gov{\textquoteright}t2004/05/05 05:00Genome Res. 2004 May;14(5):802-11.

}, month = {May}, pages = {802-11}, abstract = {

We compare the functional spectrum of protein evolution in two separate animal lineages with respect to two hypotheses: (1) rates of divergence are distributed similarly among functional classes within both lineages, indicating that selective pressure on the proteome is largely independent of organismic-level biological requirements; and (2) rates of divergence are distributed differently among functional classes within each lineage, indicating species-specific selective regimes impact genome-wide substitutional patterns. Integrating comparative genome sequence with data from tissue-specific expressed-sequence-tag (EST) libraries and detailed database annotations, we find a functional genomic signature of rapid evolution and selective constraint shared between mammalian and nematode lineages despite their extensive morphological and ecological differences and distant common ancestry. In both phyla, we find evidence of accelerated evolution among components of molecular systems involved in coevolutionary change. In mammals, lineage-specific fast evolving genes include those involved in reproduction, immunity, and possibly, maternal-fetal conflict. Likelihood ratio tests provide evidence for positive selection in these rapidly evolving functional categories in mammals. In contrast, slowly evolving genes, in terms of amino acid or insertion/deletion (indel) change, in both phyla are involved in core molecular processes such as transcription, translation, and protein transport. Thus, strong purifying selection appears to act on the same core cellular processes in both mammalian and nematode lineages, whereas positive and/or relaxed selection acts on different biological processes in each lineage.

}, keywords = {*Evolution, Molecular, Amino Acid Substitution/genetics, Animals, Caenorhabditis elegans Proteins/*physiology, Caenorhabditis elegans/genetics/immunology, Caenorhabditis/genetics, Databases, Protein, Genes, Helminth/genetics/immunology, Genes/physiology, Humans, Mice, Mutagenesis, Insertional/genetics, Organ Specificity/genetics, Phylogeny, Proteins/*physiology, Rats, Selection, Genetic, Sequence Deletion/genetics}, isbn = {1088-9051 (Print)1088-9051 (Linking)}, author = {Castillo-Davis, C. I. and Kondrashov, F. A. and Hartl, D. L. and Kulathinal, R. J.} } @article {539706, title = {Identification of a locus under complex positive selection in Drosophila simulans by haplotype mapping and composite-likelihood estimation}, journal = {Genetics}, volume = {168}, number = {1}, year = {2004}, note = {

Meiklejohn, Colin DKim, YuseobHartl, Daniel LParsch, JohnengGM60035/GM/NIGMS NIH HHS/Comparative StudyResearch Support, Non-U.S. Gov{\textquoteright}tResearch Support, U.S. Gov{\textquoteright}t, Non-P.H.S.Research Support, U.S. Gov{\textquoteright}t, P.H.S.2004/09/30 05:00Genetics. 2004 Sep;168(1):265-79.

}, month = {Sep}, pages = {265-79}, abstract = {

The recent action of positive selection is expected to influence patterns of intraspecific DNA sequence variation in chromosomal regions linked to the selected locus. These effects include decreased polymorphism, increased linkage disequilibrium, and an increased frequency of derived variants. These effects are all expected to dissipate with distance from the selected locus due to recombination. Therefore, in regions of high recombination, it should be possible to localize a target of selection to a relatively small interval. Previously described patterns of intraspecific variation in three tandemly arranged, testes-expressed genes (janusA, janusB, and ocnus) in Drosophila simulans included all three of these features. Here we expand the original sample and also survey nucleotide polymorphism at three neighboring loci. On the basis of recombination events between derived and ancestral alleles, we localize the target of selection to a 1.5-kb region surrounding janusB. A composite-likelihood-ratio test based on the spatial distribution and frequency of derived polymorphic variants corroborates this result and provides an estimate of the strength of selection. However, the data are difficult to reconcile with the simplest model of positive selection, whereas a new composite-likelihood method suggests that the data are better described by a model in which the selected allele has not yet gone to fixation.

}, keywords = {*Genetics, Population, *Models, Genetic, *Polymorphism, Genetic, *Selection, Genetic, Animals, Base Sequence, Computer Simulation, Drosophila Proteins/*genetics, Drosophila/*genetics, Haplotypes/genetics, Likelihood Functions, Molecular Sequence Data, Sequence Alignment, Sequence Analysis, DNA}, isbn = {0016-6731 (Print)0016-6731 (Linking)}, author = {Meiklejohn, C. D. and Kim, Y. and Hartl, D. L. and Parsch, J.} } @article {539201, title = {The origin of malaria: mixed messages from genetic diversity}, journal = {Nat Rev Microbiol}, volume = {2}, number = {1}, year = {2004}, note = {

Hartl, Daniel LengResearch Support, Non-U.S. Gov{\textquoteright}tResearch Support, U.S. Gov{\textquoteright}t, P.H.S.ReviewEngland2004/03/24 05:00Nat Rev Microbiol. 2004 Jan;2(1):15-22.

}, month = {Jan}, pages = {15-22}, abstract = {

Over the past 35 years, the incidence of malaria has increased 2-3-fold. At present, it affects 300-500 million people and causes about 1 million deaths, primarily in Africa. The continuing upsurge has come from a coincidence of drug-resistant parasites, insecticide-resistant mosquitoes, global climate change and continuing poverty and political instability. An analogous rapid increase in malaria might have taken place about 10,000 years ago. Patterns of genetic variation in mitochondrial DNA support this model, but variation in nuclear genes gives an ambiguous message. Resolving these discrepancies has implications for the evolution of drug resistance and vaccine evasion.

}, keywords = {*Evolution, Molecular, *Genetic Variation, Animals, DNA, Mitochondrial/genetics, Humans, Incidence, Malaria, Falciparum/*epidemiology/parasitology, Plasmodium falciparum/classification/*genetics/pathogenicity, Protozoan Proteins/genetics}, isbn = {1740-1526 (Print)1740-1526 (Linking)}, author = {Hartl, D. L.} } @article {539561, title = {Regulatory evolution across the protein interaction network}, journal = {Nat Genet}, volume = {36}, number = {10}, year = {2004}, note = {

Lemos, BernardoMeiklejohn, Colin DHartl, Daniel LengResearch Support, U.S. Gov{\textquoteright}t, P.H.S.2004/09/21 05:00Nat Genet. 2004 Oct;36(10):1059-60. Epub 2004 Sep 19.

}, month = {Oct}, pages = {1059-60}, abstract = {

Protein-protein interactions may impose constraints on both structural and regulatory evolution. Here we show that protein-protein interactions are negatively associated with evolutionary variation in gene expression. Moreover, interacting proteins have similar levels of variation in expression, and their expression levels are positively correlated across strains. Our results suggest that interacting proteins undergo similar evolutionary dynamics, and that their expression levels are evolutionarily coupled. These patterns hold for organisms as diverse as budding yeast and fruit flies.

}, keywords = {*Evolution, Molecular, Animals, Drosophila melanogaster/genetics/metabolism, Drosophila Proteins/genetics/metabolism, Gene Expression, Genes, Fungal, Genes, Insect, Genetic Variation, Genetics, Population, Male, Polymorphism, Genetic, Proteins/*genetics/*metabolism, Saccharomyces cerevisiae Proteins/genetics/metabolism, Saccharomyces cerevisiae/genetics/metabolism}, isbn = {1061-4036 (Print)1061-4036 (Linking)}, author = {Lemos, B. and Meiklejohn, C. D. and Hartl, D. L.} } @article {539996, title = {Bayesian analysis suggests that most amino acid replacements in Drosophila are driven by positive selection}, journal = {J Mol Evol}, volume = {57 Suppl 1}, year = {2003}, note = {

Sawyer, Stanley AKulathinal, Rob JBustamante, Carlos DHartl, Daniel LengGM60035/GM/NIGMS NIH HHS/GM65169/GM/NIGMS NIH HHS/Comparative StudyResearch Support, Non-U.S. Gov{\textquoteright}tResearch Support, U.S. Gov{\textquoteright}t, Non-P.H.S.Research Support, U.S. Gov{\textquoteright}t, P.H.S.2004/03/11 05:00J Mol Evol. 2003;57 Suppl 1:S154-64.

}, pages = {S154-64}, abstract = {

One of the principal goals of population genetics is to understand the processes by which genetic variation within species (polymorphism) becomes converted into genetic differences between species (divergence). In this transformation, selective neutrality, near neutrality, and positive selection may each play a role, differing from one gene to the next. Synonymous nucleotide sites are often used as a uniform standard of comparison across genes on the grounds that synonymous sites are subject to relatively weak selective constraints and so may, to a first approximation, be regarded as neutral. Synonymous sites are also interdigitated with nonsynonymous sites and so are affected equally by genomic context and demographic factors. Hence a comparison of levels of polymorphism and divergence between synonymous sites and amino acid replacement sites in a gene is potentially informative about the magnitude of selective forces associated with amino acid replacements. We have analyzed 56 genes in which polymorphism data from D. simulans are compared with divergence from a reference strain of D. melanogaster. The framework of the analysis is Bayesian and assumes that the distribution of selective effects (Malthusian fitnesses) is Gaussian with a mean that differs for each gene. In such a model, the average scaled selection intensity (gamma = N(e)s) of amino acid replacements eligible to become polymorphic or fixed is -7.31, and the standard deviation of selective effects within each locus is 6.79 (assuming homoscedasticity across loci). For newly arising mutations of this type that occur in autosomal or X-linked genes, the average proportion of beneficial mutations is 19.7\%. Among the amino acid polymorphisms in the sample, the expected average proportion of beneficial mutations is 47.7\%, and among amino acid replacements that become fixed the average proportion of beneficial mutations is 94.3\%. The average scaled selection intensity of fixed mutations is +5.1. The presence of positive selection is pervasive with the single exception of kl-5, a Y-linked fertility gene. We find no evidence that a significant fraction of fixed amino acid replacements is neutral or nearly neutral or that positive selection drives amino acid replacements at only a subset of the loci. These results are model dependent and we discuss possible modifications of the model that might allow more neutral and nearly neutral amino acid replacements to be fixed.

}, keywords = {*Bayes Theorem, *Polymorphism, Genetic, *Selection, Genetic, Amino Acid Substitution, Animals, Drosophila/*genetics, Models, Genetic, Mutation, X Chromosome, Y Chromosome}, isbn = {0022-2844 (Print)0022-2844 (Linking)}, author = {Sawyer, S. A. and Kulathinal, R. J. and Bustamante, C. D. and Hartl, D. L.} } @article {538761, title = {Conservation, relocation and duplication in genome evolution}, journal = {Trends Genet}, volume = {19}, number = {11}, year = {2003}, note = {

Castillo-Davis, Cristian IHartl, Daniel LengGM 065169/GM/NIGMS NIH HHS/GM 60035/GM/NIGMS NIH HHS/Research Support, U.S. Gov{\textquoteright}t, P.H.S.England2003/10/31 05:00Trends Genet. 2003 Nov;19(11):593-7.

}, month = {Nov}, pages = {593-7}, keywords = {*Biological Evolution, *Conserved Sequence, *Gene Duplication, *Genome, Animals, Base Sequence, Humans, Multigene Family, Selection, Genetic, X Chromosome}, isbn = {0168-9525 (Print)0168-9525 (Linking)}, author = {Castillo-Davis, C. I. and Hartl, D. L.} } @article {538546, title = {DNA sequence artifacts and the estimation of time to the most recent common ancestor (TMRCA) of Plasmodium falciparum}, journal = {Mol Biochem Parasitol}, volume = {130}, number = {2}, year = {2003}, note = {

Barry, Alyssa ELeliwa, AleksandraChoi, MeheeNielsen, Kaare MHartl, Daniel LDay, Karen PengResearch Support, Non-U.S. Gov{\textquoteright}tResearch Support, U.S. Gov{\textquoteright}t, P.H.S.Netherlands2003/08/30 05:00Mol Biochem Parasitol. 2003 Aug 31;130(2):143-7.

}, month = {Aug 31}, pages = {143-7}, keywords = {*Artifacts, *Biological Evolution, *Polymorphism, Single Nucleotide, Animals, DNA, Protozoan/chemistry/genetics, Genes, Protozoan, Genetic Variation, Genome, Protozoan, Plasmodium falciparum/*genetics, Repetitive Sequences, Nucleic Acid, Sequence Analysis, DNA/*methods, Time}, isbn = {0166-6851 (Print)0166-6851 (Linking)}, author = {Barry, A. E. and Leliwa, A. and Choi, M. and Nielsen, K. M. and Hartl, D. L. and Day, K. P.} } @article {538786, title = {Evidence for S. cerevisiae fermentation in ancient wine}, journal = {J Mol Evol}, volume = {57 Suppl 1}, year = {2003}, note = {

Cavalieri, DuccioMcGovern, Patrick EHartl, Daniel LMortimer, RobertPolsinelli, Marioeng2004/03/11 05:00J Mol Evol. 2003;57 Suppl 1:S226-32.

}, pages = {S226-32}, abstract = {

Saccharomyces cerevisiae is the principal yeast used in modern fermentation processes, including winemaking, breadmaking, and brewing. From residue present inside one of the earliest known wine jars from Egypt, we have extracted, amplified, and sequenced ribosomal DNA from S. cerevisiae. These results indicate that this organism was probably responsible for wine fermentation by at least 3150 B.C. This inference has major implications for the evolution of bread and beer yeasts, since it suggests that S. cerevisiae yeast, which occurs naturally on the surface bloom of grapes, was also used as an inoculum to ferment cereal products.

}, keywords = {*Wine, Base Sequence, DNA Primers, DNA, Fungal/isolation \& purification, DNA, Ribosomal, Egypt, Fermentation, Molecular Sequence Data, Polymerase Chain Reaction/methods, Saccharomyces cerevisiae/*genetics, Selection, Genetic, Sequence Homology, Nucleic Acid}, isbn = {0022-2844 (Print)0022-2844 (Linking)}, author = {Cavalieri, D. and McGovern, P. E. and Hartl, D. L. and Mortimer, R. and Polsinelli, M.} } @article {539766, title = {Gene conversion as a source of nucleotide diversity in Plasmodium falciparum}, journal = {Mol Biol Evol}, volume = {20}, number = {5}, year = {2003}, note = {

Nielsen, Kaare MKasper, JacobChoi, MeheeBedford, TrevorKristiansen, KurtWirth, Dyann FVolkman, Sarah KLozovsky, Elena RHartl, Daniel LengComparative StudyResearch Support, Non-U.S. Gov{\textquoteright}t2003/04/08 05:00Mol Biol Evol. 2003 May;20(5):726-34. Epub 2003 Apr 2.

}, month = {May}, pages = {726-34}, abstract = {

Examination of polymorphisms in the Plasmodium falciparum gene for falcipain 2 revealed that this gene is one of two paralogs separated by 10.8 kb in chromosome 11. We designate the annotated gene denoted chr11.gen_424 as encoding falcipain 2A and the annotated gene denoted chr11.gen_427 as encoding falcipain 2B. The paralogs are 96\% identical at the nucleotide level and 93\% identical at the amino acid level. The consensus sequences differ in 31/309 synonymous sites and 45/1140 nonsynonymous sites, including three amino acid replacements (V393I, A400P, and Q414E) that are near the catalytic site and that may affect substrate affinity or specificity. In six reference isolates, among 36 synonymous sites and 46 nonsynonymous sites that are polymorphic in the gene for falcipain 2A, falcipain 2B, or both, significant spatial clustering is observed. All but one of the polymorphisms appear to result from gene conversion between the paralogs. The estimated rate of gene conversion between the paralogs may be as many as 1,400 to 1,700 times greater than the rate of mutation. Owing to gene conversion, one of the falcipain 2A alleles is more similar to the falcipain 2B alleles than it is to other falcipain 2A alleles. Divergence among the synonymous sites suggests that the paralogous genes last shared a common ancestor 15.2 MYA, with a range of 8.8 to 20.6 MYA. During this period, the paralogs have acquired 0.10 synonymous substitutions per synonymous site in the coding region. The 5{\textquoteright} and 3{\textquoteright} flanking regions differ in 47.7\% and 39.8\% of the nucleotide sites, respectively. Hence synonymous sites and flanking regions are not conserved in sequence in spite of their high AT content and T skew.

}, keywords = {*Evolution, Molecular, *Gene Conversion, *Genes, Duplicate, *Genetic Variation, Animals, Base Sequence, Cluster Analysis, Cysteine Endopeptidases/*genetics, DNA Primers, Models, Molecular, Molecular Sequence Data, Plasmodium falciparum/*genetics, Protein Conformation, Sequence Alignment}, isbn = {0737-4038 (Print)0737-4038 (Linking)}, author = {Nielsen, K. M. and Kasper, J. and Choi, M. and Bedford, T. and Kristiansen, K. and Wirth, DF and Volkman, S. K. and Lozovsky, E. R. and Hartl, D. L.} } @article {538766, title = {GeneMerge--post-genomic analysis, data mining, and hypothesis testing}, journal = {Bioinformatics}, volume = {19}, number = {7}, year = {2003}, note = {

Castillo-Davis, Cristian IHartl, Daniel LengEnglandOxford, England2003/05/02 05:00Bioinformatics. 2003 May 1;19(7):891-2.

}, month = {May 1}, pages = {891-2}, abstract = {

SUMMARY: GeneMerge is a web-based and standalone program written in PERL that returns a range of functional and genomic data for a given set of study genes and provides statistical rank scores for over-representation of particular functions or categories in the data set. Functional or categorical data of all kinds can be analyzed with GeneMerge, facilitating regulatory and metabolic pathway analysis, tests of population genetic hypotheses, cross-experiment comparisons, and tests of chromosomal clustering, among others. GeneMerge can perform analyses on a wide variety of genomic data quickly and easily and facilitates both data mining and hypothesis testing. AVAILABILITY: GeneMerge is available free of charge for academic use over the web and for download from: http://www.oeb.harvard.edu/hartl/lab/publications/GeneMerge.html.

}, keywords = {*Algorithms, *Database Management Systems, *Genome, Gene Expression Profiling/*methods, Genetics, Population, Information Storage and Retrieval/*methods, Models, Genetic, Models, Statistical, Sequence Alignment/*methods, Sequence Analysis, DNA/*methods, Software}, isbn = {1367-4803 (Print)1367-4803 (Linking)}, author = {Castillo-Davis, C. I. and Hartl, D. L.} } @article {540051, title = {Genetic dissection of hybrid incompatibilities between Drosophila simulans and D. mauritiana. I. Differential accumulation of hybrid male sterility effects on the X and autosomes}, journal = {Genetics}, volume = {164}, number = {4}, year = {2003}, note = {

Tao, YunChen, SiningHartl, Daniel LLaurie, Cathy CengNIH 47292/PHS HHS/NIH 65169/PHS HHS/Comparative StudyResearch Support, Non-U.S. Gov{\textquoteright}tResearch Support, U.S. Gov{\textquoteright}t, P.H.S.2003/08/22 05:00Genetics. 2003 Aug;164(4):1383-97.

}, month = {Aug}, pages = {1383-97}, abstract = {

The genetic basis of hybrid incompatibility in crosses between Drosophila mauritiana and D. simulans was investigated to gain insight into the evolutionary mechanisms of speciation. In this study, segments of the D. mauritiana third chromosome were introgressed into a D. simulans genetic background and tested as homozygotes for viability, male fertility, and female fertility. The entire third chromosome was covered with partially overlapping segments. Many segments were male sterile, while none were female sterile or lethal, confirming previous reports of the rapid evolution of hybrid male sterility (HMS). A statistical model was developed to quantify the HMS accumulation. In comparison with previous work on the X chromosome, we estimate that the X has approximately 2.5 times the density of HMS factors as the autosomes. We also estimate that the whole genome contains approximately 15 HMS "equivalents"-i.e., 15 times the minimum number of incompatibility factors necessary to cause complete sterility. Although some caveats for the quantitative estimate of a 2.5-fold density difference are described, this study supports the notion that the X chromosome plays a special role in the evolution of reproductive isolation. Possible mechanisms of a "large X" effect include selective fixation of new mutations that are recessive or partially recessive and the evolution of sex-ratio distortion systems.

}, keywords = {*Chromosomes, *Hybridization, Genetic, *X Chromosome, Animals, Biological Evolution, Biological Markers, Cell Survival, Crosses, Genetic, Drosophila/*genetics, Female, Fertility/genetics, Genes, Insect, Homozygote, Infertility, Male/*genetics, Male, Models, Genetic, Sex Factors, Species Specificity, Y Chromosome}, isbn = {0016-6731 (Print)0016-6731 (Linking)}, author = {Tao, Y. and Chen, S. and Hartl, D. L. and Laurie, C. C.} } @article {540056, title = {Genetic dissection of hybrid incompatibilities between Drosophila simulans and D. mauritiana. III. Heterogeneous accumulation of hybrid incompatibilities, degree of dominance, and implications for Haldane{\textquoteright}s rule}, journal = {Evolution}, volume = {57}, number = {11}, year = {2003}, note = {

Tao, YunHartl, Daniel Leng47292/PHS HHS/65169/PHS HHS/Comparative StudyResearch Support, Non-U.S. Gov{\textquoteright}tResearch Support, U.S. Gov{\textquoteright}t, P.H.S.2003/12/23 05:00Evolution. 2003 Nov;57(11):2580-98.

}, month = {Nov}, pages = {2580-98}, abstract = {

The genetic basis of Haldane{\textquoteright}s rule was investigated through estimating the accumulation of hybrid incompatibilities between Drosophila simulans and D. mauritiana by means of introgression. The accumulation of hybrid male sterility (HMS) is at least 10 times greater than that of hybrid female sterility (HFS) or hybrid lethality (HL). The degree of dominance for HMS and HL in a pure D. simulans background is estimated as 0.23-0.29 and 0.33-0.39, respectively; that for HL in an F1 background is unlikely to be very small. Evidence obtained here was used to test the Turelli-Orr model of Haldane{\textquoteright}s rule. Composite causes, especially, faster-male evolution and recessive hybrid incompatibilities, underlie Haldane{\textquoteright}s rule in heterogametic male taxa such as Drosophila (XY male and XX female). However, if faster-male evolution is driven by sexual selection, it contradicts Haldane{\textquoteright}s rule for sterility in heterogametic-female taxa such as Lepidoptera (ZW female and ZZ male). The hypothesis of a faster-heterogametic-sex evolution seems to fit the current data best. This hypothesis states that gametogenesis in the heterogametic sex, instead of in males per se, evolves much faster than in the homogametic sex, in part because of sex-ratio selection. This hypothesis not only explains Haldane{\textquoteright}s rule in a simple way, but also suggests that genomic conflicts play a major role in evolution and speciation.

}, keywords = {*Biological Evolution, *Genetics, Population, *Hybridization, Genetic, *Models, Genetic, Animals, Crosses, Genetic, Drosophila/*genetics, Reproduction/physiology, Selection, Genetic, Sex Factors}, isbn = {0014-3820 (Print)0014-3820 (Linking)}, author = {Tao, Y. and Hartl, D. L.} } @article {540071, title = {Genetic dissection of hybrid incompatibilities between Drosophila simulans and D. mauritiana. II. Mapping hybrid male sterility loci on the third chromosome}, journal = {Genetics}, volume = {164}, number = {4}, year = {2003}, note = {

Tao, YunZeng, Zhao-BangLi, JianHartl, Daniel LLaurie, Cathy CengNIH 47292/PHS HHS/NIH 65169/PHS HHS/Comparative StudyResearch Support, Non-U.S. Gov{\textquoteright}tResearch Support, U.S. Gov{\textquoteright}t, P.H.S.2003/08/22 05:00Genetics. 2003 Aug;164(4):1399-418.

}, month = {Aug}, pages = {1399-418}, abstract = {

Hybrid male sterility (HMS) is a rapidly evolving mechanism of reproductive isolation in Drosophila. Here we report a genetic analysis of HMS in third-chromosome segments of Drosophila mauritiana that were introgressed into a D. simulans background. Qualitative genetic mapping was used to localize 10 loci on 3R and a quantitative trait locus (QTL) procedure (multiple-interval mapping) was used to identify 19 loci on the entire chromosome. These genetic incompatibilities often show dominance and complex patterns of epistasis. Most of the HMS loci have relatively small effects and generally at least two or three of them are required to produce complete sterility. Only one small region of the third chromosome of D. mauritiana by itself causes a high level of infertility when introgressed into D. simulans. By comparison with previous studies of the X chromosome, we infer that HMS loci are only approximately 40\% as dense on this autosome as they are on the X chromosome. These results are consistent with the gradual evolution of hybrid incompatibilities as a by-product of genetic divergence in allopatric populations.

}, keywords = {*Alleles, *Hybridization, Genetic, Animals, Biological Evolution, Biological Markers, Chromosome Mapping, Chromosomes/*genetics, Crosses, Genetic, Drosophila/*genetics, Epistasis, Genetic, Genes, Dominant, Genetic Variation, Infertility, Male/*genetics, Lod Score, Male, Quantitative Trait Loci, Recombination, Genetic, Sex Factors, Species Specificity, X Chromosome, Y Chromosome}, isbn = {0016-6731 (Print)0016-6731 (Linking)}, author = {Tao, Y. and Zeng, Z. B. and J. Li and Hartl, D. L. and Laurie, C. C.} } @article {540161, title = {Genetic diversity in yeast assessed with whole-genome oligonucleotide arrays}, journal = {Genetics}, volume = {163}, number = {1}, year = {2003}, note = {

Winzeler, Elizabeth ACastillo-Davis, Cristian IOshiro, GuyLiang, DavidRichards, Daniel RZhou, YingyaoHartl, Daniel Leng2003/02/15 04:00Genetics. 2003 Jan;163(1):79-89.

}, month = {Jan}, pages = {79-89}, abstract = {

The availability of a complete genome sequence allows the detailed study of intraspecies variability. Here we use high-density oligonucleotide arrays to discover 11,115 single-feature polymorphisms (SFPs) existing in one or more of 14 different yeast strains. We use these SFPs to define regions of genetic identity between common laboratory strains of yeast. We assess the genome-wide distribution of genetic variation on the basis of this yeast population. We find that genome variability is biased toward the ends of chromosomes and is more likely to be found in genes with roles in fermentation or in transport. This subtelomeric bias may arise through recombination between nonhomologous sequences because full-gene deletions are more common in these regions than in more central regions of the chromosome.

}, keywords = {*Genetic Variation, Chromosome Mapping, Oligonucleotide Array Sequence Analysis, Phylogeny, Polymorphism, Genetic, Saccharomyces cerevisiae/*genetics, Telomere}, isbn = {0016-6731 (Print)0016-6731 (Linking)}, author = {Winzeler, E. A. and Castillo-Davis, C. I. and Oshiro, G. and Liang, D. and Richards, D. R. and Zhou, Y. and Hartl, D. L.} } @article {540096, title = {Horizontal acquisition of divergent chromosomal DNA in bacteria: effects of mutator phenotypes}, journal = {Genetics}, volume = {164}, number = {1}, year = {2003}, note = {

Townsend, Jeffrey PNielsen, Kaare MFisher, Daniel SHartl, Daniel LengResearch Support, Non-U.S. Gov{\textquoteright}tResearch Support, U.S. Gov{\textquoteright}t, Non-P.H.S.Research Support, U.S. Gov{\textquoteright}t, P.H.S.2003/05/17 05:00Genetics. 2003 May;164(1):13-21.

}, month = {May}, pages = {13-21}, abstract = {

We examine the potential beneficial effects of the expanded access to environmental DNA offered by mutators on the adaptive potential of bacterial populations. Using parameters from published studies of recombination in E. coli, we find that the presence of mutators has the potential to greatly enhance bacterial population adaptation when compared to populations without mutators. In one specific example, for which three specific amino acid substitutions are required for adaptation to occur in a 300-amino-acid protein, we found a 3500-fold increase in the rate of adaptation. The probability of a beneficial acquisition decreased if more amino acid changes, or integration of longer DNA fragments, were required for adaptation. The model also predicts that mutators are more likely than nonmutator phenotypes to acquire genetic variability from a more diverged set of donor bacteria. Bacterial populations harboring mutators in a sequence heterogeneous environment are predicted to acquire most of their DNA conferring adaptation in the range of 13-30\% divergence, whereas nonmutator phenotypes become adapted after recombining with more homogeneous sequences of 7-21\% divergence. We conclude that mutators can accelerate bacterial adaptation when desired genetic variability is present within DNA fragments of up to approximately 30\% divergence.

}, keywords = {*Gene Transfer, Horizontal, *Genetic Variation, Data Interpretation, Statistical, Escherichia coli/*genetics, Evolution, Molecular, Models, Genetic}, isbn = {0016-6731 (Print)0016-6731 (Linking)}, author = {Townsend, J. P. and Nielsen, K. M. and Fisher, DS and Hartl, D. L.} } @article {538681, title = {Maximum likelihood and Bayesian methods for estimating the distribution of selective effects among classes of mutations using DNA polymorphism data}, journal = {Theor Popul Biol}, volume = {63}, number = {2}, year = {2003}, note = {

Bustamante, Carlos DNielsen, RasmusHartl, Daniel Leng2003/03/05 04:00Theor Popul Biol. 2003 Mar;63(2):91-103.

}, month = {Mar}, pages = {91-103}, abstract = {

Maximum likelihood and Bayesian approaches are presented for analyzing hierarchical statistical models of natural selection operating on DNA polymorphism within a panmictic population. For analyzing Bayesian models, we present Markov chain Monte-Carlo (MCMC) methods for sampling from the joint posterior distribution of parameters. For frequentist analysis, an Expectation-Maximization (EM) algorithm is presented for finding the maximum likelihood estimate of the genome wide mean and variance in selection intensity among classes of mutations. The framework presented here provides an ideal setting for modeling mutations dispersed through the genome and, in particular, for the analysis of how natural selection operates on different classes of single nucleotide polymorphisms (SNPs).

}, keywords = {*Bayes Theorem, *Likelihood Functions, *Mutation, *Polymorphism, Single Nucleotide, *Selection, Genetic, DNA/*genetics, Genetics, Population, Poisson Distribution, United States}, isbn = {0040-5809 (Print)0040-5809 (Linking)}, author = {Bustamante, C. D. and Nielsen, R. and Hartl, D. L.} } @article {539911, title = {Origin and evolution of a new gene expressed in the Drosophila sperm axoneme}, journal = {Genetica}, volume = {118}, number = {2-3}, year = {2003}, note = {

Ranz, Jose MariaPonce, Ana RitaHartl, Daniel LNurminsky, Dmitryeng60035/PHS HHS/GM61549/GM/NIGMS NIH HHS/Research Support, Non-U.S. Gov{\textquoteright}tResearch Support, U.S. Gov{\textquoteright}t, P.H.S.Netherlands2003/07/19 05:00Genetica. 2003 Jul;118(2-3):233-44.

}, month = {Jul}, pages = {233-44}, abstract = {

Sdic is a new gene that evolved recently in the lineage of Drosophila melanogaster. It was formed from a duplication and fusion of the gene AnnX, which encodes annexin X, and Cdic, which encodes the intermediate polypeptide chain of the cytoplasmic dynein. The fusion joins AnnX exon 4 with Cdic intron 3, which brings together three putative promoter elements for testes-specific expression of Sdic: the distal conserved element (DCE) and testes-specific element (TSE) are derived from AnnX, and the proximal conserved element (PCE) from Cdic intron 3. Sdic transcription initiates within the PCE, and translation is initiated within the sequence derived from Cdic intron 3, continuing through a 10 base pair insertion that creates a new splice donor site that enables the new coding sequence derived from intron 3 to be joined with the coding sequence of Cdic exon 4. A novel protein is created lacking 100 residues at the amino end that contain sequence motifs essential for the function of cytoplasmic dynein intermediate chains. Instead, the amino end is a hydrophobic region of 16 residues that resembles the amino end of axonemal dynein intermediate chains from other organisms. The downstream portion of Sdic features large deletions eliminating Cdic exons v2 and v3, as well as multiple frameshift deletions or insertions. The new protein becomes incorporated into the tail of the mature sperm and may function as an axonemal dynein intermediate chain. The new Sdic gene is present in about 10 tandem repeats between the wildtype Cdic and AnnX genes located near the base of the X chromosome. The implications of these findings are discussed relative to the origin of new gene functions and the process of speciation.

}, keywords = {*Drosophila Proteins, Amino Acid Sequence, Animals, Artificial Gene Fusion, Axonemal Dyneins, Chromosome Mapping, Drosophila melanogaster/*genetics, Dyneins/*genetics, Evolution, Molecular, Exons, Genes, Insect/*genetics, Introns, Male, Molecular Sequence Data, Sperm Tail/metabolism}, isbn = {0016-6707 (Print)0016-6707 (Linking)}, author = {Ranz, J. M. and Ponce, A. R. and Hartl, D. L. and Nurminsky, D.} } @article {540131, title = {Parasitology. A game of cat and mouth}, journal = {Science}, volume = {299}, number = {5605}, year = {2003}, note = {

Volkman, Sarah KHartl, Daniel LengCommentNew York, N.Y.2003/01/18 04:00Science. 2003 Jan 17;299(5605):353-4.

}, month = {Jan 17}, pages = {353-4}, keywords = {*Biological Evolution, Animals, Cat Diseases/parasitology/transmission, Cats, Female, Food Parasitology, Genes, Protozoan, Genetic Variation, Humans, Life Cycle Stages, Mice, Mouth, Mutation, Polymorphism, Genetic, Pregnancy, Pregnancy Complications, Parasitic/parasitology, Recombination, Genetic, Reproduction, Toxoplasma/*genetics/pathogenicity/*physiology, Toxoplasmosis, Animal/*parasitology/transmission, Toxoplasmosis, Congenital/epidemiology/parasitology, Toxoplasmosis/*parasitology/transmission, Virulence}, isbn = {1095-9203 (Electronic)0036-8075 (Linking)}, author = {Volkman, S. K. and Hartl, D. L.} } @article {540081, title = {Population genetic variation in genome-wide gene expression}, journal = {Mol Biol Evol}, volume = {20}, number = {6}, year = {2003}, note = {

Townsend, Jeffrey PCavalieri, DuccioHartl, Daniel LengResearch Support, Non-U.S. Gov{\textquoteright}t2003/04/30 05:00Mol Biol Evol. 2003 Jun;20(6):955-63. Epub 2003 Apr 25.

}, month = {Jun}, pages = {955-63}, abstract = {

Evolutionary biologists seek to understand which traits display variation, are heritable, and influence differential reproduction, because such traits respond to natural selection and underlie organic evolution. Selection acts upon individual differences within a population. Whether individual differences within a natural population include variation in gene expression levels has not yet been addressed on a genome-wide scale. Here we use DNA microarray technology for measuring comparative gene expression and a refined statistical analysis for the purpose of comparing gene expression levels in natural isolates of the wine yeast Saccharomyces cerevisiae. A method for the Bayesian analysis of gene expression levels is used to compare four natural isolates of S. cerevisiae from Montalcino, Italy. Widespread variation in amino acid metabolism, sulfur assimilation and processing, and protein degradation-primarily consisting of differences in expression level smaller than a factor of 2-is demonstrated. Genetic variation in gene expression among isolates from a natural population is present on a genomic scale. It remains to be determined what role differential gene expression may play in adaptation to new or changing environments.

}, keywords = {*Gene Expression, *Genetics, Population, *Genome, Fungal, DNA Transposable Elements, Evolution, Molecular, Fungal Proteins/metabolism, Metals/metabolism, Oligonucleotide Array Sequence Analysis, Open Reading Frames, Saccharomyces cerevisiae/*genetics/metabolism}, isbn = {0737-4038 (Print)0737-4038 (Linking)}, author = {Townsend, J. P. and Cavalieri, D. and Hartl, D. L.} } @article {539711, title = {Rapid evolution of male-biased gene expression in Drosophila}, journal = {Proc Natl Acad Sci U S A}, volume = {100}, number = {17}, year = {2003}, note = {

Meiklejohn, Colin DParsch, JohnRanz, Jose MHartl, Daniel LengGM 60035/GM/NIGMS NIH HHS/Comparative StudyResearch Support, Non-U.S. Gov{\textquoteright}tResearch Support, U.S. Gov{\textquoteright}t, P.H.S.2003/08/09 05:00Proc Natl Acad Sci U S A. 2003 Aug 19;100(17):9894-9. Epub 2003 Aug 7.

}, month = {Aug 19}, pages = {9894-9}, abstract = {

A number of genes associated with sexual traits and reproduction evolve at the sequence level faster than the majority of genes coding for non-sex-related traits. Whole genome analyses allow this observation to be extended beyond the limited set of genes that have been studied thus far. We use cDNA microarrays to demonstrate that this pattern holds in Drosophila for the phenotype of gene expression as well, but in one sex only. Genes that are male-biased in their expression show more variation in relative expression levels between conspecific populations and two closely related species than do female-biased genes or genes with sexually monomorphic expression patterns. Additionally, elevated ratios of interspecific expression divergence to intraspecific expression variation among male-biased genes suggest that differences in rates of evolution may be due in part to natural selection. This finding has implications for our understanding of the importance of sexual dimorphism for speciation and rates of phenotypic evolution.

}, keywords = {*Biological Evolution, *Genes, Insect, *Sex, Animals, Drosophila melanogaster/genetics, Drosophila/*genetics, Female, Gene Expression Profiling, Male, Oligonucleotide Array Sequence Analysis, Sex Characteristics, Species Specificity}, isbn = {0027-8424 (Print)0027-8424 (Linking)}, author = {Meiklejohn, C. D. and Parsch, J. and Ranz, J. M. and Hartl, D. L.} } @article {539901, title = {Sex-dependent gene expression and evolution of the Drosophila transcriptome}, journal = {Science}, volume = {300}, number = {5626}, year = {2003}, note = {

Ranz, Jose MCastillo-Davis, Cristian IMeiklejohn, Colin DHartl, Daniel LengComparative StudyResearch Support, Non-U.S. Gov{\textquoteright}tResearch Support, U.S. Gov{\textquoteright}t, P.H.S.New York, N.Y.2003/06/14 05:00Science. 2003 Jun 13;300(5626):1742-5.

}, month = {Jun 13}, pages = {1742-5}, abstract = {

Comparison of the gene-expression profiles between adults of Drosophila melanogaster and Drosophila simulans has uncovered the evolution of genes that exhibit sex-dependent regulation. Approximately half the genes showed differences in expression between the species, and among these, approximately 83\% involved a gain, loss, increase, decrease, or reversal of sex-biased expression. Most of the interspecific differences in messenger RNA abundance affect male-biased genes. Genes that differ in expression between the species showed functional clustering only if they were sex-biased. Our results suggest that sex-dependent selection may drive changes in expression of many of the most rapidly evolving genes in the Drosophila transcriptome.

}, keywords = {*Evolution, Molecular, *Gene Expression, *Genome, *Transcription, Genetic, Animals, Bayes Theorem, Drosophila melanogaster/*genetics, Drosophila/*genetics, Female, Gene Expression Profiling, Genes, Insect, Male, Mutation, Nucleic Acid Hybridization, Oligonucleotide Array Sequence Analysis, RNA, Messenger/genetics/metabolism, Selection, Genetic, Sex Characteristics, Species Specificity, X Chromosome/genetics}, isbn = {1095-9203 (Electronic)0036-8075 (Linking)}, author = {Ranz, J. M. and Castillo-Davis, C. I. and Meiklejohn, C. D. and Hartl, D. L.} } @article {540091, title = {Bayesian analysis of gene expression levels: statistical quantification of relative mRNA level across multiple strains or treatments}, journal = {Genome Biol}, volume = {3}, number = {12}, year = {2002}, note = {

Townsend, Jeffrey PHartl, Daniel Leng60035/PHS HHS/HG02150/HG/NHGRI NIH HHS/Comparative StudyResearch Support, Non-U.S. Gov{\textquoteright}tResearch Support, U.S. Gov{\textquoteright}t, P.H.S.England2003/01/23 04:00Genome Biol. 2002;3(12):RESEARCH0071. Epub 2002 Nov 20.

}, pages = {RESEARCH0071}, abstract = {

BACKGROUND: Methods of microarray analysis that suit experimentalists using the technology are vital. Many methodologies discard the quantitative results inherent in cDNA microarray comparisons or cannot be flexibly applied to multifactorial experimental design. Here we present a flexible, quantitative Bayesian framework. This framework can be used to analyze normalized microarray data acquired by any replicated experimental design in which any number of treatments, genotypes, or developmental states are studied using a continuous chain of comparisons. RESULTS: We apply this method to Saccharomyces cerevisiae microarray datasets on the transcriptional response to ethanol shock, to SNF2 and SWI1 deletion in rich and minimal media, and to wild-type and zap1 expression in media with high, medium, and low levels of zinc. The method is highly robust to missing data, and yields estimates of the magnitude of expression differences and experimental error variances on a per-gene basis. It reveals genes of interest that are differentially expressed at below the twofold level, genes with high {\textquoteright}fold-change{\textquoteright} that are not statistically significantly different, and genes differentially regulated in quantitatively unanticipated ways. CONCLUSIONS: Anyone with replicated normalized cDNA microarray ratio datasets can use the freely available MacOS and Windows software, which yields increased biological insight by taking advantage of replication to discern important changes in expression level both above and below a twofold threshold. Not only does the method have utility at the moment, but also, within the Bayesian framework, there will be considerable opportunity for future development.

}, keywords = {*Nuclear Proteins, Bayes Theorem, DNA-Binding Proteins/genetics, Ethanol/pharmacology, Gene Deletion, Gene Expression Profiling/methods/*statistics \& numerical data, Gene Expression Regulation, Fungal/drug effects/*genetics/physiology, Genotype, Models, Genetic, Oligonucleotide Array Sequence Analysis/methods/*statistics \& numerical data, RNA, Fungal/*metabolism, RNA, Messenger/*biosynthesis, Saccharomyces cerevisiae Proteins/*biosynthesis/*genetics, Species Specificity, Transcription Factors/genetics, Zinc}, isbn = {1465-6914 (Electronic)1465-6906 (Linking)}, author = {Townsend, J. P. and Hartl, D. L.} } @article {538686, title = {The cost of inbreeding in Arabidopsis}, journal = {Nature}, volume = {416}, number = {6880}, year = {2002}, note = {

Bustamante, Carlos DNielsen, RasmusSawyer, Stanley AOlsen, Kenneth MPurugganan, Michael DHartl, Daniel LengResearch Support, Non-U.S. Gov{\textquoteright}tResearch Support, U.S. Gov{\textquoteright}t, Non-P.H.S.Research Support, U.S. Gov{\textquoteright}t, P.H.S.England2002/04/05 10:00Nature. 2002 Apr 4;416(6880):531-4.

}, month = {Apr 4}, pages = {531-4}, abstract = {

Population geneticists have long sought to estimate the distribution of selection intensities among genes of diverse function across the genome. Only recently have DNA sequencing and analytical techniques converged to make this possible. Important advances have come from comparing genetic variation within species (polymorphism) with fixed differences between species (divergence). These approaches have been used to examine individual genes for evidence of selection. Here we use the fact that the time since species divergence allows combination of data across genes. In a comparison of amino-acid replacements among species of the mustard weed Arabidopsis with those among species of the fruitfly Drosophila, we find evidence for predominantly beneficial gene substitutions in Drosophila but predominantly detrimental substitutions in Arabidopsis. We attribute this difference to the Arabidopsis mating system of partial self-fertilization, which corroborates a prediction of population genetics theory that species with a high frequency of inbreeding are less efficient in eliminating deleterious mutations owing to their reduced effective population size.

}, keywords = {*Inbreeding, Amino Acid Substitution, Animals, Arabidopsis/*genetics/physiology, Biological Evolution, Drosophila/genetics, Genes, Plant, Models, Genetic, Polymorphism, Genetic, Selection, Genetic}, isbn = {0028-0836 (Print)0028-0836 (Linking)}, author = {Bustamante, C. D. and Nielsen, R. and Sawyer, S. A. and Olsen, K. M. and Purugganan, M. D. and Hartl, D. L.} } @article {539606, title = {Efficient mobilization of mariner in vivo requires multiple internal sequences}, journal = {Genetics}, volume = {160}, number = {2}, year = {2002}, note = {

Lohe, Allan RHartl, Daniel LengGM33741/GM/NIGMS NIH HHS/GM58423/GM/NIGMS NIH HHS/Research Support, U.S. Gov{\textquoteright}t, P.H.S.2002/02/28 10:00Genetics. 2002 Feb;160(2):519-26.

}, month = {Feb}, pages = {519-26}, abstract = {

Aberrant products of mariner excision that have an impaired ability to be mobilized often include internal deletions that do not encroach on either of the inverted repeats. Analysis of 13 such deletions, as well as 7 additional internal deletions obtained by various methods, has revealed at least three internal regions whose integrity is necessary for efficient mariner mobilization. Within the 1286-bp element, the essential regions are contained in the intervals bounded by coordinates 229-586, 735-765, and 939-1066, numbering in base pairs from the extreme 5{\textquoteright} end of the element. These regions may contain sequences that are necessary for transposase binding or that are needed to maintain proper spacing between binding sites. The isolation of excision-defective elements with point mutations at nucleotide positions 993 and 161/179 supports the hypothesis of sequence requirements, but the reduced mobility of transformation vectors with insertions into the SacI site at position 790 supports the hypothesis of spacing requirements. The finding of multiple internal regions that are essential for efficient mariner mobilization in vivo contrasts with reports that mini-elements with as little as 43 bp of DNA between the inverted repeats can transpose efficiently in vitro.

}, keywords = {Animals, DNA Transposable Elements/*genetics/physiology, DNA-Binding Proteins/*genetics/physiology, Drosophila melanogaster/*genetics/physiology, Female, Gene Deletion, Male, Transposases/*genetics/physiology}, isbn = {0016-6731 (Print)0016-6731 (Linking)}, author = {Lohe, A. R. and Hartl, D. L.} } @article {540136, title = {Excess polymorphisms in genes for membrane proteins in Plasmodium falciparum}, journal = {Science}, volume = {298}, number = {5591}, year = {2002}, note = {

Volkman, Sarah KHartl, Daniel LWirth, Dyann FNielsen, Kaare MChoi, MeheeBatalov, SergeZhou, YingyaoPlouffe, DavidLe Roch, Karine GAbagyan, RubenWinzeler, Elizabeth AengGM61351/GM/NIGMS NIH HHS/Research Support, Non-U.S. Gov{\textquoteright}tResearch Support, U.S. Gov{\textquoteright}t, Non-P.H.S.Research Support, U.S. Gov{\textquoteright}t, P.H.S.New York, N.Y.2002/10/05 04:00Science. 2002 Oct 4;298(5591):216-8.

}, month = {Oct 4}, pages = {216-8}, abstract = {

The detection of single-nucleotide polymorphisms in pathogenic microorganisms has normally been carried out by trial and error. Here we show that DNA hybridization with high-density oligonucleotide arrays provides rapid and convenient detection of single-nucleotide polymorphisms in Plasmodium falciparum, despite its exceptionally high adenine-thymine (AT) content (82\%). A disproportionate number of polymorphisms are found in genes encoding proteins associated with the cell membrane. These genes are targets for only 22\% of the oligonucleotide probes but account for 69\% of the polymorphisms. Genetic variation is also enriched in subtelomeric regions, which account for 22\% of the chromosome but 76\% of the polymorphisms.

}, keywords = {*Genes, Protozoan, *Polymorphism, Single Nucleotide, Animals, Base Sequence, Chromosomes/genetics, DNA, Protozoan/genetics, Genetic Variation, Genome, Protozoan, Membrane Proteins/*genetics, Molecular Sequence Data, Nucleic Acid Hybridization, Oligonucleotide Probes, Plasmodium falciparum/*genetics, Protozoan Proteins/*genetics, Sequence Analysis, DNA}, isbn = {1095-9203 (Electronic)0036-8075 (Linking)}, author = {Volkman, S. K. and Hartl, D. L. and Wirth, DF and Nielsen, K. M. and Choi, M. and Batalov, S. and Zhou, Y. and Plouffe, D. and Le Roch, K. G. and Abagyan, R. and Winzeler, E. A.} } @article {538756, title = {Genome evolution and developmental constraint in Caenorhabditis elegans}, journal = {Mol Biol Evol}, volume = {19}, number = {5}, year = {2002}, note = {

Castillo-Davis, Cristian IHartl, Daniel LengGM 0035/GM/NIGMS NIH HHS/GM 58423/GM/NIGMS NIH HHS/Comparative StudyResearch Support, U.S. Gov{\textquoteright}t, P.H.S.2002/04/19 10:00Mol Biol Evol. 2002 May;19(5):728-35.

}, month = {May}, pages = {728-35}, abstract = {

It has been hypothesized that evolutionary changes will be more frequent in later ontogeny than early ontogeny because of developmental constraint. To test this hypothesis, a genomewide examination of molecular evolution through ontogeny was carried out using comparative genomic data in Caenorhabditis elegans and Caenorhabditis briggsae. We found that the mean rate of amino acid replacement is not significantly different between genes expressed during and after embryogenesis. However, synonymous substitution rates differed significantly between these two classes. A genomewide survey of correlation between codon bias and expression level found codon bias to be significantly correlated with mRNA expression (r(s) = -0.30 and P \< 10(-131)) but does not alone explain differences in dS between classes. Surprisingly, it was found that genes expressed after embryogenesis have a significantly greater number of duplicates in both the C. elegans and C. briggsae genomes (P \< 10(-20) and P \< 10(-13)) when compared with early-expressed and nonmodulated genes. A similarity in the distribution of duplicates of nonmodulated and early-expressed genes, as well as a disproportionately higher number of early pseudogenes, lend support to the hypothesis that this difference in duplicate number is caused by selection against gene duplicates of early-expressed genes, reflecting developmental constraint. Developmental constraint at the level of gene duplication may have important implications for macroevolutionary change.

}, keywords = {*Evolution, Molecular, *Genome, Amino Acid Substitution, Animals, Caenorhabditis elegans Proteins/genetics, Caenorhabditis elegans/*genetics/*growth \& development, Caenorhabditis/genetics/growth \& development, Codon/genetics, Gene Duplication, Gene Expression Profiling, Gene Expression Regulation, Developmental, Genes, Helminth, Models, Genetic, Pseudogenes}, isbn = {0737-4038 (Print)0737-4038 (Linking)}, author = {Castillo-Davis, C. I. and Hartl, D. L.} } @article {538676, title = {A maximum likelihood method for analyzing pseudogene evolution: implications for silent site evolution in humans and rodents}, journal = {Mol Biol Evol}, volume = {19}, number = {1}, year = {2002}, note = {

Bustamante, Carlos DNielsen, RasmusHartl, Daniel LengResearch Support, Non-U.S. Gov{\textquoteright}t2001/12/26 10:00Mol Biol Evol. 2002 Jan;19(1):110-7.

}, month = {Jan}, pages = {110-7}, abstract = {

We present a new likelihood method for detecting constrained evolution at synonymous sites and other forms of nonneutral evolution in putative pseudogenes. The model is applicable whenever the DNA sequence is available from a protein-coding functional gene, a pseudogene derived from the protein-coding gene, and an orthologous functional copy of the gene. Two nested likelihood ratio tests are developed to test the hypotheses that (1) the putative pseudogene has equal rates of silent and replacement substitutions; and (2) the rate of synonymous substitution in the functional gene equals the rate of substitution in the pseudogene. The method is applied to a data set containing 74 human processed-pseudogene loci, 25 mouse processed-pseudogene loci, and 22 rat processed-pseudogene loci. Using the informatics resources of the Human Genome Project, we localized 67 of the human-pseudogene pairs in the genome and estimated the GC content of a large surrounding genomic region for each. We find that, for pseudogenes deposited in GC regions similar to those of their paralogs, the assumption of equal rates of silent and replacement site evolution in the pseudogene is upheld; in these cases, the rate of silent site evolution in the functional genes is approximately 70\% the rate of evolution in the pseudogene. On the other hand, for pseudogenes located in genomic regions of much lower GC than their functional gene, we see a sharp increase in the rate of silent site substitutions, leading to a large rate of rejection for the pseudogene equality likelihood ratio test.

}, keywords = {*Evolution, Molecular, Animals, Base Composition/genetics, Cytosine/metabolism, Guanine/metabolism, Humans, Likelihood Functions, Logistic Models, Mice, Phylogeny, Pseudogenes/*genetics, Rats}, isbn = {0737-4038 (Print)0737-4038 (Linking)}, author = {Bustamante, C. D. and Nielsen, R. and Hartl, D. L.} } @article {539381, title = {The paradoxical population genetics of Plasmodium falciparum}, journal = {Trends Parasitol}, volume = {18}, number = {6}, year = {2002}, note = {

Hartl, Daniel LVolkman, Sarah KNielsen, Kaare MBarry, Alyssa EDay, Karen PWirth, Dyann FWinzeler, Elizabeth AengGM61351/GM/NIGMS NIH HHS/Research Support, Non-U.S. Gov{\textquoteright}tResearch Support, U.S. Gov{\textquoteright}t, P.H.S.ReviewEngland2002/05/31 10:00Trends Parasitol. 2002 Jun;18(6):266-72.

}, month = {Jun}, pages = {266-72}, abstract = {

Among the leading causes of death in African children is cerebral malaria caused by the parasitic protozoan Plasmodium falciparum. Endemic forms of this disease are thought to have originated in central Africa 5000-10000 years ago, coincident with the innovation of slash-and-burn agriculture and the diversification of the Anopheles gambiae complex of mosquito vectors. Population genetic studies of P. falciparum have yielded conflicting results. Some evidence suggests that today{\textquoteright}s population includes multiple ancient lineages pre-dating human speciation. Other evidence suggests that today{\textquoteright}s population derives from only one, or a small number, of these ancient lineages. Resolution of this issue is important for the evaluation of the long-term efficacy of drug and immunological control strategies.

}, keywords = {Animals, Anopheles/parasitology, Endemic Diseases, Evolution, Molecular, Genetic Variation, Humans, Malaria, Falciparum/epidemiology/parasitology, Plasmodium falciparum/*genetics/growth \& development}, isbn = {1471-4922 (Print)1471-4922 (Linking)}, author = {Hartl, D. L. and Volkman, S. K. and Nielsen, K. M. and Barry, A. E. and Day, K. P. and Wirth, DF and Winzeler, E. A.} } @article {539046, title = {Pathway Processor: a tool for integrating whole-genome expression results into metabolic networks}, journal = {Genome Res}, volume = {12}, number = {7}, year = {2002}, note = {

Grosu, PaulTownsend, Jeffrey PHartl, Daniel LCavalieri, DuccioengComparative Study2002/07/05 10:00Genome Res. 2002 Jul;12(7):1121-6.

}, month = {Jul}, pages = {1121-6}, abstract = {

We have developed a new tool to visualize expression data on metabolic pathways and to evaluate which metabolic pathways are most affected by transcriptional changes in whole-genome expression experiments. Using the Fisher Exact Test, the method scores biochemical pathways according to the probability that as many or more genes in a pathway would be significantly altered in a given experiment by chance alone. This method has been validated on diauxic shift experiments and reproduces well known effects of carbon source on yeast metabolism. The analysis is implemented with Pathway Analyzer, one of the tools of Pathway Processor, a new statistical package for the analysis of whole-genome expression data. Results from multiple experiments can be compared, reducing the analysis from the full set of individual genes to a limited number of pathways of interest. The pathways are visualized with OpenDX, an open-source visualization software package, and the relationship between genes in the pathways can be examined in detail using Expression Mapper, the second program of the package. This program features a graphical output displaying differences in expression on metabolic charts of the biochemical pathways to which the open reading frames are assigned.

}, keywords = {*Gene Expression Profiling/instrumentation/methods/statistics \& numerical data, *Genome, Fungal, *Software/statistics \& numerical data, Energy Metabolism/*genetics, Gene Expression Regulation, Fungal/genetics, Genes, Fungal/genetics/physiology, Saccharomyces cerevisiae/*genetics/*metabolism, Transcription, Genetic/genetics/physiology}, isbn = {1088-9051 (Print)1088-9051 (Linking)}, author = {Grosu, P. and Townsend, J. P. and Hartl, D. L. and Cavalieri, D.} } @article {538601, title = {Patterns of insertion and deletion in contrasting chromatin domains}, journal = {Mol Biol Evol}, volume = {19}, number = {12}, year = {2002}, note = {

Blumenstiel, Justin PHartl, Daniel LLozovsky, Elena RengGM 58423/GM/NIGMS NIH HHS/Research Support, U.S. Gov{\textquoteright}t, P.H.S.2002/11/26 04:00Mol Biol Evol. 2002 Dec;19(12):2211-25.

}, month = {Dec}, pages = {2211-25}, abstract = {

Transposable elements (TEs) play a fundamental role in the evolution of genomes. In Drosophila they are disproportionately represented in regions of low recombination, such as in heterochromatin. This pattern has been attributed to selection against repeated elements in regions of normal recombination, owing to either (1) the slightly deleterious position effects of TE insertions near or into genes, or (2) strong selection against chromosomal abnormalities arising from ectopic exchange between TE repeats. We have used defective non-long-terminal repeat (LTR) TEs that are "dead-on-arrival" (DOA) and unable to transpose in order to estimate spontaneous deletion rates in different constituents of chromatin. These elements have previously provided evidence for an extremely high rate of spontaneous deletion in Drosophila as compared with mammals, potentially explaining at least part of the differences in the genome sizes in these organisms. However, rates of deletion could be overestimated due to positive selection for a smaller likelihood of ectopic exchange. In this article, we show that rates of spontaneous deletion in DOA repeats are as high in heterochromatin and regions of euchromatin with low recombination as they are in regions of euchromatin with normal recombination. We have also examined the age distribution of five non-LTR families throughout the genome. We show that there is substantial variation in the historical pattern of transposition of these TEs. The overrepresentation of TEs in the heterochromatin is primarily due to their longer retention time in heterochromatin, as evidenced by the average time since insertion. Fragments inserted recently are much more evenly distributed in the genome. This contrast demonstrates that the accumulation of TEs in heterochromatin and in euchromatic regions of low recombination is not due to biased transposition but by greater probabilities of fixation in these regions relative to regions of normal recombination.

}, keywords = {*Sequence Deletion, Animals, Chromatin/chemistry/*genetics, DNA/genetics, Drosophila melanogaster/genetics, genome, Polymorphism, Genetic}, isbn = {0737-4038 (Print)0737-4038 (Linking)}, author = {Blumenstiel, J. P. and Hartl, D. L. and Lozovsky, E. R.} } @article {538781, title = {Selection for short introns in highly expressed genes}, journal = {Nat Genet}, volume = {31}, number = {4}, year = {2002}, note = {

Castillo-Davis, Cristian IMekhedov, Sergei LHartl, Daniel LKoonin, Eugene VKondrashov, Fyodor Aeng2002/07/23 10:00Nat Genet. 2002 Aug;31(4):415-8. Epub 2002 Jul 22.

}, month = {Aug}, pages = {415-8}, abstract = {

Transcription is a slow and expensive process: in eukaryotes, approximately 20 nucleotides can be transcribed per second at the expense of at least two ATP molecules per nucleotide. Thus, at least for highly expressed genes, transcription of long introns, which are particularly common in mammals, is costly. Using data on the expression of genes that encode proteins in Caenorhabditis elegans and Homo sapiens, we show that introns in highly expressed genes are substantially shorter than those in genes that are expressed at low levels. This difference is greater in humans, such that introns are, on average, 14 times shorter in highly expressed genes than in genes with low expression, whereas in C. elegans the difference in intron length is only twofold. In contrast, the density of introns in a gene does not strongly depend on the level of gene expression. Thus, natural selection appears to favor short introns in highly expressed genes to minimize the cost of transcription and other molecular processes, such as splicing.

}, keywords = {*Gene Expression Regulation, *Genome, Human, *Introns, *Selection, Genetic, Animals, Caenorhabditis elegans Proteins/genetics, Caenorhabditis elegans/*genetics, DNA Transposable Elements, Expressed Sequence Tags, Humans, Transcription, Genetic}, isbn = {1061-4036 (Print)1061-4036 (Linking)}, author = {Castillo-Davis, C. I. and Mekhedov, S. L. and Hartl, D. L. and Koonin, E. V. and Kondrashov, F. A.} } @article {539656, title = {Unexpected stability of mariner transgenes in Drosophila}, journal = {Genetics}, volume = {160}, number = {2}, year = {2002}, note = {

Lozovsky, Elena RNurminsky, DmitryWimmer, Ernst AHartl, Daniel LengGM33741/GM/NIGMS NIH HHS/GM58423/GM/NIGMS NIH HHS/GM60035/GM/NIGMS NIH HHS/GM61549/GM/NIGMS NIH HHS/HG02150/HG/NHGRI NIH HHS/Research Support, Non-U.S. Gov{\textquoteright}tResearch Support, U.S. Gov{\textquoteright}t, P.H.S.2002/02/28 10:00Genetics. 2002 Feb;160(2):527-35.

}, month = {Feb}, pages = {527-35}, abstract = {

A number of mariner transformation vectors based on the mauritiana subfamily of transposable elements were introduced into the genome of Drosophila melanogaster and examined for their ability to be mobilized by the mariner transposase. Simple insertion vectors were constructed from single mariner elements into which exogenous DNA ranging in size from 1.3 to 4.5 kb had been inserted; composite vectors were constructed with partial or complete duplications of mariner flanking the exogenous DNA. All of the simple insertion vectors showed levels of somatic and germline excision that were at least 100-fold lower than the baseline level of uninterrupted mariner elements. Although composite vectors with inverted duplications were unable to be mobilized at detectable frequencies, vectors with large direct duplications of mariner could be mobilized. A vector consisting of two virtually complete elements flanking exogenous DNA yielded a frequency of somatic eye-color mosaicism of approximately 10\% and a frequency of germline excision of 0.04\%. These values are far smaller than those observed for uninterrupted elements. The results imply that efficient mobilization of mariner in vivo requires the presence and proper spacing of sequences internal to the element as well as the inverted repeats.

}, keywords = {Animals, Animals, Genetically Modified/*genetics, DNA-Binding Proteins/*genetics, Drosophila melanogaster/*genetics, Female, Genes, Insect, Genetic Vectors/genetics, Male, Mosaicism/genetics, Transgenes, Transposases}, isbn = {0016-6731 (Print)0016-6731 (Linking)}, author = {Lozovsky, E. R. and Nurminsky, D. and Wimmer, E. A. and Hartl, D. L.} } @article {539771, title = {Chromosomal effects of rapid gene evolution in Drosophila melanogaster}, journal = {Science}, volume = {291}, number = {5501}, year = {2001}, note = {

Nurminsky, DAguiar, D DBustamante, C DHartl, D LengGM 60035/GM/NIGMS NIH HHS/Research Support, U.S. Gov{\textquoteright}t, P.H.S.New York, N.Y.2001/01/06 11:00Science. 2001 Jan 5;291(5501):128-30.

}, month = {Jan 5}, pages = {128-30}, abstract = {

Rapid adaptive fixation of a new favorable mutation is expected to affect neighboring genes along the chromosome. Evolutionary theory predicts that the chromosomal region would show a reduced level of genetic variation and an excess of rare alleles. We have confirmed these predictions in a region of the X chromosome of Drosophila melanogaster that contains a newly evolved gene for a component of the sperm axoneme. In D. simulans, where the novel gene does not exist, the pattern of genetic variation is consistent with selection against recurrent deleterious mutations. These findings imply that the pattern of genetic variation along a chromosome may be useful for inferring its evolutionary history and for revealing regions in which recent adaptive fixations have taken place.

}, keywords = {*Drosophila Proteins, *Evolution, Molecular, *Genes, Insect, *Genetic Variation, Alleles, Animals, Axonemal Dyneins, Drosophila melanogaster/*genetics, Drosophila/genetics, Dyneins/*genetics, Likelihood Functions, Logistic Models, Mutation, Polymorphism, Genetic, Selection, Genetic, X Chromosome/*genetics}, isbn = {0036-8075 (Print)0036-8075 (Linking)}, author = {Nurminsky, D. and Aguiar, D. D. and Bustamante, C. D. and Hartl, D. L.} } @article {538696, title = {Directional selection and the site-frequency spectrum}, journal = {Genetics}, volume = {159}, number = {4}, year = {2001}, note = {

Bustamante, C DWakeley, JSawyer, SHartl, D LengResearch Support, Non-U.S. Gov{\textquoteright}tResearch Support, U.S. Gov{\textquoteright}t, Non-P.H.S.2002/01/10 10:00Genetics. 2001 Dec;159(4):1779-88.

}, month = {Dec}, pages = {1779-88}, abstract = {

In this article we explore statistical properties of the maximum-likelihood estimates (MLEs) of the selection and mutation parameters in a Poisson random field population genetics model of directional selection at DNA sites. We derive the asymptotic variances and covariance of the MLEs and explore the power of the likelihood ratio tests (LRT) of neutrality for varying levels of mutation and selection as well as the robustness of the LRT to deviations from the assumption of free recombination among sites. We also discuss the coverage of confidence intervals on the basis of two standard-likelihood methods. We find that the LRT has high power to detect deviations from neutrality and that the maximum-likelihood estimation performs very well when the ancestral states of all mutations in the sample are known. When the ancestral states are not known, the test has high power to detect deviations from neutrality for negative selection but not for positive selection. We also find that the LRT is not robust to deviations from the assumption of independence among sites.

}, keywords = {*Models, Genetic, *Recombination, Genetic, Alleles, Likelihood Functions, Models, Statistical, Poisson Distribution}, isbn = {0016-6731 (Print)0016-6731 (Linking)}, author = {Bustamante, C. D. and J. Wakeley and Sawyer, S. and Hartl, D. L.} } @article {538576, title = {Genomic gigantism: DNA loss is slow in mountain grasshoppers}, journal = {Mol Biol Evol}, volume = {18}, number = {2}, year = {2001}, note = {

Bensasson, DPetrov, D AZhang, D XHartl, D LHewitt, G MengGM58423/GM/NIGMS NIH HHS/Comparative StudyResearch Support, Non-U.S. Gov{\textquoteright}tResearch Support, U.S. Gov{\textquoteright}t, P.H.S.2001/02/07 11:00Mol Biol Evol. 2001 Feb;18(2):246-53.

}, month = {Feb}, pages = {246-53}, abstract = {

Several studies have shown DNA loss to be inversely correlated with genome size in animals. These studies include a comparison between Drosophila and the cricket, Laupala, but there has been no assessment of DNA loss in insects with very large genomes. Podisma pedestris, the brown mountain grasshopper, has a genome over 100 times as large as that of Drosophila and 10 times as large as that of Laupala. We used 58 paralogous nuclear pseudogenes of mitochondrial origin to study the characteristics of insertion, deletion, and point substitution in P. pedestris and Italopodisma. In animals, these pseudogenes are "dead on arrival"; they are abundant in many different eukaryotes, and their mitochondrial origin simplifies the identification of point substitutions accumulated in nuclear pseudogene lineages. There appears to be a mononucleotide repeat within the 643-bp pseudogene sequence studied that acts as a strong hot spot for insertions or deletions (indels). Because the data for other insect species did not contain such an unusual region, hot spots were excluded from species comparisons. The rate of DNA loss relative to point substitution appears to be considerably and significantly lower in the grasshoppers studied than in Drosophila or Laupala. This suggests that the inverse correlation between genome size and the rate of DNA loss can be extended to comparisons between insects with large or gigantic genomes (i.e., Laupala and Podisma). The low rate of DNA loss implies that in grasshoppers, the accumulation of point mutations is a more potent force for obscuring ancient pseudogenes than their loss through indel accumulation, whereas the reverse is true for Drosophila. The main factor contributing to the difference in the rates of DNA loss estimated for grasshoppers, crickets, and Drosophila appears to be deletion size. Large deletions are relatively rare in Podisma and Italopodisma.

}, keywords = {*Genome, Animals, Base Sequence, Cell Nucleus/genetics, DNA, Mitochondrial/*genetics, Drosophila/genetics, Evolution, Molecular, Genes, Insect/*genetics, Grasshoppers/*genetics, Gryllidae/genetics, Molecular Sequence Data, Mutation, Phylogeny, Polymerase Chain Reaction, Pseudogenes/genetics, Sequence Alignment, Sequence Deletion, Sequence Homology, Nucleic Acid, Species Specificity}, isbn = {0737-4038 (Print)0737-4038 (Linking)}, author = {Bensasson, D. and Petrov, D. A. and Zhang, D. X. and Hartl, D. L. and Hewitt, G. M.} } @article {538581, title = {Mitochondrial pseudogenes: evolution{\textquoteright}s misplaced witnesses}, journal = {Trends Ecol Evol}, volume = {16}, number = {6}, year = {2001}, note = {

Bensasson, DZhang, D -X.Hartl, D L.Hewitt, G M.ENG2001/05/23 10:00Trends Ecol Evol. 2001 Jun 1;16(6):314-321.

}, month = {Jun 1}, pages = {314-321}, abstract = {

Nuclear copies of mitochondrial DNA (mtDNA) have contaminated PCR-based mitochondrial studies of over 64 different animal species. Since the last review of these nuclear mitochondrial pseudogenes (Numts) in animals, Numts have been found in 53 of the species studied. The recent evidence suggests that Numts are not equally abundant in all species, for example they are more common in plants than in animals, and also more numerous in humans than in Drosophila. Methods for avoiding Numts have now been tested, and several recent studies demonstrate the potential utility of Numt DNA sequences in evolutionary studies. As relics of ancient mtDNA, these pseudogenes can be used to infer ancestral states or root mitochondrial phylogenies. Where they are numerous and selectively unconstrained, Numts are ideal for the study of spontaneous mutation in nuclear genomes.

}, isbn = {1872-8383 (Electronic)0169-5347 (Linking)}, author = {Bensasson, D. and Zhang, D. and Hartl, D. L. and Hewitt, G. M.} } @article {539841, title = {Molecular evolution of the ocnus and janus genes in the Drosophila melanogaster species subgroup}, journal = {Mol Biol Evol}, volume = {18}, number = {5}, year = {2001}, note = {

Parsch, JMeiklejohn, C DHauschteck-Jungen, EHunziker, PHartl, D LengGM60035/GM/NIGMS NIH HHS/HG01250/HG/NHGRI NIH HHS/Research Support, U.S. Gov{\textquoteright}t, P.H.S.2001/04/25 10:00Mol Biol Evol. 2001 May;18(5):801-11.

}, month = {May}, pages = {801-11}, abstract = {

Genes involved in male fertility are potential targets for sexual selection, and their evolution may play a role in reproductive isolation and speciation. Here we describe a new Drosophila melanogaster gene, ocnus (ocn), that encodes a protein abundant in testes nuclear extracts. RT-PCR indicates that ocn transcription is limited to males and is specific to testes. ocn shares homology with another testis-specific gene, janusB (janB), and is located just distal to janB on chromosome 3. The two genes also share homology with the adjacent janusA (janA) gene, suggesting that multiple duplication events have occurred within this region of the genome. We cloned and sequenced these three genes from species of the D. melanogaster species subgroup. Phylogenetic analysis based on protein-encoding sequences predicts a duplication pattern of janA --\> janA janB --\> janA janB ocn, with the latter event occurring after the divergence of the D. melanogaster and Drosophila obscura species groups. We found significant heterogeneity in the rates of evolution among the three genes within the D. melanogaster species subgroup as measured by the ratio of nonsynonymous to synonymous substitutions, suggesting that diversification of gene function followed each duplication event and that each gene evolved under different selective constraints. All three genes showed faster rates of evolution than genes encoding proteins with metabolic function. These results are consistent with previous studies that have detected an increased rate of evolution in genes with reproductive function.

}, keywords = {*Drosophila melanogaster/*genetics, *Evolution, Molecular, *Genes, Insect, Animals, Drosophila, Expressed Sequence Tags, Gene Expression Regulation, Gene Library, Genes, Duplicate, Likelihood Functions, Male, Models, Genetic, Molecular Sequence Data, Nucleoproteins/*chemistry/*genetics, Phylogeny, Reverse Transcriptase Polymerase Chain Reaction, Sensitivity and Specificity, Sequence Analysis, DNA, Sequence Analysis, Protein, Testis/chemistry, Transcription, Genetic}, isbn = {0737-4038 (Print)0737-4038 (Linking)}, author = {Parsch, J. and Meiklejohn, C. D. and Hauschteck-Jungen, E. and Hunziker, P. and Hartl, D. L.} } @article {539836, title = {Patterns of DNA sequence variation suggest the recent action of positive selection in the janus-ocnus region of Drosophila simulans}, journal = {Genetics}, volume = {159}, number = {2}, year = {2001}, note = {

Parsch, JMeiklejohn, C DHartl, D LengGM60035/GM/NIGMS NIH HHS/HG01250/HG/NHGRI NIH HHS/Research Support, U.S. Gov{\textquoteright}t, P.H.S.2001/10/19 10:00Genetics. 2001 Oct;159(2):647-57.

}, month = {Oct}, pages = {647-57}, abstract = {

Levels of nucleotide polymorphism in three paralogous Drosophila simulans genes, janusA (janA), janusB (janB), and ocnus (ocn), were surveyed by DNA sequencing. The three genes lie in tandem within a 2.5-kb region of chromosome arm 3R. In a sample of eight alleles from a worldwide distribution we found a significant departure from neutrality by several statistical tests. The most striking feature of this sample was that in a 1.7-kb region containing the janA and janB genes, 30 out of 31 segregating sites contained variants present only once in the sample, and 29 of these unique variants were found in the same allele. A restriction survey of an additional 28 lines of D. simulans revealed strong linkage disequilibrium over the janA-janB region and identified six more alleles matching the rare haplotype. Among the rare alleles, the level of DNA sequence variation was typical for D. simulans autosomal genes and showed no departure from neutrality. In addition, the rare haplotype was more similar to the D. melanogaster sequence, indicating that it was the ancestral form. These results suggest that the derived haplotype has risen to high worldwide frequency relatively recently, most likely as a result of natural selection.

}, keywords = {*Drosophila Proteins, *Selection, Genetic, *Sequence Analysis, DNA, Animals, Base Sequence, Chromosome Mapping, DNA Primers, Drosophila/*genetics, Insect Proteins/*genetics, Linkage Disequilibrium, Polymerase Chain Reaction, Polymorphism, Genetic, Sequence Homology, Nucleic Acid}, isbn = {0016-6731 (Print)0016-6731 (Linking)}, author = {Parsch, J. and Meiklejohn, C. D. and Hartl, D. L.} } @article {540126, title = {Recent origin of Plasmodium falciparum from a single progenitor}, journal = {Science}, volume = {293}, number = {5529}, year = {2001}, note = {

Volkman, S KBarry, A ELyons, E JNielsen, K MThomas, S MChoi, MThakore, S SDay, K PWirth, D FHartl, D LengResearch Support, Non-U.S. Gov{\textquoteright}tResearch Support, U.S. Gov{\textquoteright}t, P.H.S.New York, N.Y.2001/07/21 10:00Science. 2001 Jul 20;293(5529):482-4.

}, month = {Jul 20}, pages = {482-4}, abstract = {

Genetic variability of Plasmodium falciparum underlies its transmission success and thwarts efforts to control disease caused by this parasite. Genetic variation in antigenic, drug resistance, and pathogenesis determinants is abundant, consistent with an ancient origin of P. falciparum, whereas DNA variation at silent (synonymous) sites in coding sequences appears virtually absent, consistent with a recent origin of the parasite. To resolve this paradox, we analyzed introns and demonstrated that these are deficient in single-nucleotide polymorphisms, as are synonymous sites in coding regions. These data establish the recent origin of P. falciparum and further provide an explanation for the abundant diversity observed in antigen and other selected genes.

}, keywords = {*Biological Evolution, *Genetic Variation, *Introns, *Microsatellite Repeats, *Polymorphism, Single Nucleotide, Africa, Agriculture, Alternative Splicing, Animals, Base Sequence, Genes, Protozoan, Humans, Malaria, Falciparum/epidemiology/parasitology/transmission, Molecular Sequence Data, Mutation, Plasmodium falciparum/*genetics, Plasmodium/genetics}, isbn = {0036-8075 (Print)0036-8075 (Linking)}, author = {Volkman, S. K. and Barry, A. E. and Lyons, E. J. and Nielsen, K. M. and Thomas, S. M. and Choi, M. and Thakore, S. S. and Day, K. P. and Wirth, DF and Hartl, D. L.} } @article {540061, title = {Sex-ratio segregation distortion associated with reproductive isolation in Drosophila}, journal = {Proc Natl Acad Sci U S A}, volume = {98}, number = {23}, year = {2001}, note = {

Tao, YHartl, D LLaurie, C CengGM47292/GM/NIGMS NIH HHS/GM60035/GM/NIGMS NIH HHS/Research Support, Non-U.S. Gov{\textquoteright}tResearch Support, U.S. Gov{\textquoteright}t, P.H.S.2001/11/01 10:00Proc Natl Acad Sci U S A. 2001 Nov 6;98(23):13183-8. Epub 2001 Oct 30.

}, month = {Nov 6}, pages = {13183-8}, abstract = {

Sex-ratio distortion is the most common form of non-Mendelian segregation observed in natural populations. It may occur even more frequently than direct observations suggest, because the dysgenic population consequences of a biased sex ratio are expected to result in the rapid evolution of suppressors, resulting in suppressed or "cryptic" segregation distortion. Here we report evidence for cryptic sex-ratio distortion that was discovered by introgressing segments of the genome of Drosophila mauritiana into the genome of Drosophila simulans. The autosomal suppressor of sex-ratio distortion, which is also associated with a reduction in hybrid male fertility, has been genetically localized to a region smaller than 80-kb pairs in chromosome 3.

}, keywords = {*Reproduction, *Sex Ratio, Alleles, Animals, Drosophila/genetics/*physiology, Female, Homozygote, Male}, isbn = {0027-8424 (Print)0027-8424 (Linking)}, author = {Tao, Y. and Hartl, D. L. and Laurie, C. C.} } @article {540031, title = {Application of Cre/loxP in Drosophila. Site-specific recombination and transgene coplacement}, journal = {Methods Mol Biol}, volume = {136}, year = {2000}, note = {

Siegal, M LHartl, D LengGM-33741/GM/NIGMS NIH HHS/HG-01250/HG/NHGRI NIH HHS/Research Support, Non-U.S. Gov{\textquoteright}tResearch Support, U.S. Gov{\textquoteright}t, P.H.S.ReviewClifton, N.J.2000/06/07 09:00Methods Mol Biol. 2000;136:487-95.

}, pages = {487-95}, keywords = {*Viral Proteins, Animals, Drosophila/*genetics, Integrases/*metabolism, Recombination, Genetic, Transgenes}, isbn = {1064-3745 (Print)1064-3745 (Linking)}, author = {Siegal, M. L. and Hartl, D. L.} } @article {539846, title = {Deletion of a conserved regulatory element in the Drosophila Adh gene leads to increased alcohol dehydrogenase activity but also delays development}, journal = {Genetics}, volume = {156}, number = {1}, year = {2000}, note = {

Parsch, JRussell, J ABeerman, IHartl, D LStephan, WengGM02150/GM/NIGMS NIH HHS/GM58405/GM/NIGMS NIH HHS/Research Support, U.S. Gov{\textquoteright}t, P.H.S.2000/09/09 11:00Genetics. 2000 Sep;156(1):219-27.

}, month = {Sep}, pages = {219-27}, abstract = {

In vivo levels of enzymatic activity may be increased through either structural or regulatory changes. Here we use Drosophila melanogaster alcohol dehydrogenase (ADH) in an experimental test for selective differences between these two mechanisms. The well-known ADH-Slow (S)/Fast (F) amino acid replacement leads to a twofold increase in activity by increasing the catalytic efficiency of the enzyme. Disruption of a highly conserved, negative regulatory element in the Adh 3{\textquoteright} UTR also leads to a twofold increase in activity, although this is achieved by increasing in vivo Adh mRNA and protein concentrations. These two changes appear to be under different types of selection, with positive selection favoring the amino acid replacement and purifying selection maintaining the 3{\textquoteright} UTR sequence. Using transgenic experiments we show that deletion of the conserved 3{\textquoteright} UTR element increases adult and larval Adh expression in both the ADH-F and ADH-S genetic backgrounds. However, the 3{\textquoteright} UTR deletion also leads to a significant increase in developmental time in both backgrounds. ADH allozyme type has no detectable effect on development. These results demonstrate a negative fitness effect associated with Adh overexpression. This provides a mechanism whereby natural selection can discriminate between alternative pathways of increasing enzymatic activity.

}, keywords = {*Genes, Insect, 3{\textquoteright} Untranslated Regions, Alcohol Dehydrogenase/*genetics/*metabolism, Animals, Base Sequence, Conserved Sequence, DNA Primers/genetics, Drosophila melanogaster/*enzymology/*genetics/growth \& development, Female, Genes, Regulator, Larva/enzymology/growth \& development, Male, Sequence Deletion, Tissue Distribution}, isbn = {0016-6731 (Print)0016-6731 (Linking)}, author = {Parsch, J. and Russell, J. A. and Beerman, I. and Hartl, D. L. and Stephan, W.} } @article {539881, title = {Evidence for DNA loss as a determinant of genome size}, journal = {Science}, volume = {287}, number = {5455}, year = {2000}, note = {

Petrov, D ASangster, T AJohnston, J SHartl, D LShaw, K LengResearch Support, Non-U.S. Gov{\textquoteright}tResearch Support, U.S. Gov{\textquoteright}t, Non-P.H.S.Research Support, U.S. Gov{\textquoteright}t, P.H.S.New York, N.Y.2000/02/11 09:00Science. 2000 Feb 11;287(5455):1060-2.

}, month = {Feb 11}, pages = {1060-2}, abstract = {

Eukaryotic genome sizes range over five orders of magnitude. This variation cannot be explained by differences in organismic complexity (the C value paradox). To test the hypothesis that some variation in genome size can be attributed to differences in the patterns of insertion and deletion (indel) mutations among organisms, this study examines the indel spectrum in Laupala crickets, which have a genome size 11 times larger than that of Drosophila. Consistent with the hypothesis, DNA loss is more than 40 times slower in Laupala than in Drosophila.

}, keywords = {*Evolution, Molecular, *Genome, *Mutation, *Retroelements, Animals, DNA/genetics, Drosophila/*genetics, Gryllidae/*genetics, Likelihood Functions, Multigene Family, Phylogeny, Polymerase Chain Reaction, Pseudogenes, Sequence Deletion, Species Specificity}, isbn = {0036-8075 (Print)0036-8075 (Linking)}, author = {Petrov, D. A. and Sangster, T. A. and Johnston, J. S. and Hartl, D. L. and Shaw, K. L.} } @article {539196, title = {Fly meets shotgun: shotgun wins}, journal = {Nat Genet}, volume = {24}, number = {4}, year = {2000}, note = {

Hartl, D LengNews2000/03/31 09:00Nat Genet. 2000 Apr;24(4):327-8.

}, month = {Apr}, pages = {327-8}, keywords = {*Human Genome Project, Animals, Cloning, Molecular, Drosophila melanogaster/*genetics, Physical Chromosome Mapping/trends, Sequence Analysis, DNA/*methods/trends}, isbn = {1061-4036 (Print)1061-4036 (Linking)}, author = {Hartl, D. L.} } @article {539566, title = {Identification of phylogenetic footprints in primate tumor necrosis factor-alpha promoters}, journal = {Proc Natl Acad Sci U S A}, volume = {97}, number = {12}, year = {2000}, note = {

Leung, J YMcKenzie, F EUglialoro, A MFlores-Villanueva, P OSorkin, B CYunis, E JHartl, D LGoldfeld, A EengGM56492/GM/NIGMS NIH HHS/HG-02150/HG/NHGRI NIH HHS/HL-59838/HL/NHLBI NIH HHS/Z99 TW999999/TW/FIC NIH HHS/Research Support, Non-U.S. Gov{\textquoteright}tResearch Support, U.S. Gov{\textquoteright}t, P.H.S.2000/06/07 09:00Proc Natl Acad Sci U S A. 2000 Jun 6;97(12):6614-8.

}, month = {Jun 6}, pages = {6614-8}, abstract = {

The human tumor necrosis factor-alpha (TNF-alpha) gene encodes a pleiotropic cytokine that plays a critical role in basic immunologic processes. To investigate the TNF-alpha regulatory region in the primate lineage, we isolated TNF-alpha promoters from representative great apes, Old World monkeys, and New World monkeys. We demonstrate that there is a nonuniform distribution of fixed human differences in the TNF-alpha promoter. We define a "fixed human difference" as a site that is not polymorphic in humans, but which differs in at least one of the seven primate sequences examined. Furthermore, we identify two human TNF-alpha promoter single nucleotide polymorphisms that are putative ancestral polymorphisms, because each of the human polymorphic nucleotides was found at the identical site in at least one of the other primate sequences. Strikingly, the largest conserved region among the primate species, a 69-nt "phylogenetic footprint," corresponds to a region of the human TNF-alpha promoter that forms the transcriptionally active nucleoprotein-DNA complex, essential for gene regulation. By contrast, other regions of the TNF-alpha promoter, which exhibit a high density of variable sites, are nonessential for gene expression, indicating that distinct TNF-alpha promoter regions have been subjected to different evolutionary constraints depending on their function. TNF-alpha is the first case in which a promoter region dissected by functional analyses can be correlated with nucleotide polymorphism and variability in primate lineages. The results suggest that patterns of polymorphism and divergence are likely to be useful in identifying candidate regions important for gene regulation in other immune-response genes.

}, keywords = {*Phylogeny, *Promoter Regions, Genetic, Animals, Base Sequence, Conserved Sequence, HLA-B Antigens/genetics, HLA-DR Antigens/genetics, Humans, Molecular Sequence Data, Primates/*genetics, Tumor Necrosis Factor-alpha/*genetics}, isbn = {0027-8424 (Print)0027-8424 (Linking)}, author = {Leung, J. Y. and McKenzie, F. E. and Uglialoro, A. M. and Flores-Villanueva, P. O. and Sorkin, B. C. and Yunis, E. J. and Hartl, D. L. and Goldfeld, A. E.} } @article {540086, title = {The kinetics of transposable element autoregulation}, journal = {Genetica}, volume = {108}, number = {3}, year = {2000}, note = {

Townsend, J PHartl, D LengResearch Support, U.S. Gov{\textquoteright}t, P.H.S.Netherlands2001/04/11 10:00Genetica. 2000;108(3):229-37.

}, pages = {229-37}, abstract = {

Kinetic modeling of the self-regulatory mechanisms of transposable elements (TEs) involving interactions of one or a few gene products makes predictions that are often at odds with observed results. In particular, explanations of TE autorepression at high copy number that invoke a decrease in number of active monomers through dimerization, amyloidization, and protein-mRNA binding to create an inactive state are not supported by analysis of the corresponding kinetic models. This is also true for similar mRNA-mRNA binding models. Self-repression in mariner as well as other TEs can, however, be explained by a host-independent model in which inactive dimers compete with monomers for TE binding sites at the ends of the element. This model would also allow heterodimer poisoning to down-regulate transposition in the presence of divergent nonautonomous elements, since nondivergent monomers would be required at both TE ends for transposition.

}, keywords = {*Models, Biological, Animals, DNA Transposable Elements/*genetics/*physiology, DNA-Binding Proteins/genetics/metabolism, Drosophila melanogaster/genetics/metabolism, Escherichia coli/genetics/metabolism, Homeostasis, Kinetics, RNA Processing, Post-Transcriptional, RNA, Bacterial/genetics/metabolism, RNA, Messenger/genetics/metabolism, Transposases}, isbn = {0016-6707 (Print)0016-6707 (Linking)}, author = {Townsend, J. P. and Hartl, D. L.} } @article {538791, title = {Manifold anomalies in gene expression in a vineyard isolate of Saccharomyces cerevisiae revealed by DNA microarray analysis}, journal = {Proc Natl Acad Sci U S A}, volume = {97}, number = {22}, year = {2000}, note = {

Cavalieri, DTownsend, J PHartl, D LengHG01250/HG/NHGRI NIH HHS/Research Support, Non-U.S. Gov{\textquoteright}tResearch Support, U.S. Gov{\textquoteright}t, P.H.S.2000/10/18 11:00Proc Natl Acad Sci U S A. 2000 Oct 24;97(22):12369-74.

}, month = {Oct 24}, pages = {12369-74}, abstract = {

Genome-wide transcriptional profiling has important applications in evolutionary biology for assaying the extent of heterozygosity for alleles showing quantitative variation in gene expression in natural populations. We have used DNA microarray analysis to study the global pattern of transcription in a homothallic strain of Saccharomyces cerevisiae isolated from wine grapes in a Tuscan vineyard, along with the diploid progeny obtained after sporulation. The parental strain shows 2:2 segregation (heterozygosity) for three unlinked loci. One determines resistance to trifluoroleucine; another, resistance to copper sulfate; and the third is associated with a morphological phenotype observed as colonies with a ridged surface resembling a filigree. Global expression analysis of the progeny with the filigreed and smooth colony phenotypes revealed a greater than 2-fold difference in transcription for 378 genes (6\% of the genome). A large number of the overexpressed genes function in pathways of amino acid biosynthesis (particularly methionine) and sulfur or nitrogen assimilation, whereas many of the underexpressed genes are amino acid permeases. These wholesale changes in amino acid metabolism segregate as a suite of traits resulting from a single gene or a small number of genes. We conclude that natural vineyard populations of S. cerevisiae can harbor alleles that cause massive alterations in the global patterns of gene expression. Hence, studies of expression variation in natural populations, without accompanying segregation analysis, may give a false picture of the number of segregating genes underlying the variation.

}, keywords = {*Gene Expression Profiling, *Gene Expression Regulation, Fungal, Amino Acids/biosynthesis, Ammonia/metabolism, Down-Regulation, Energy Metabolism, Genome, Fungal, Phenotype, Saccharomyces cerevisiae/*genetics/metabolism}, isbn = {0027-8424 (Print)0027-8424 (Linking)}, author = {Cavalieri, D. and Townsend, J. P. and Hartl, D. L.} } @article {539191, title = {Molecular melodies in high and low C}, journal = {Nat Rev Genet}, volume = {1}, number = {2}, year = {2000}, note = {

Hartl, D LengResearch Support, U.S. Gov{\textquoteright}t, P.H.S.ReviewEngland2001/03/20 10:00Nat Rev Genet. 2000 Nov;1(2):145-9.

}, month = {Nov}, pages = {145-9}, abstract = {

For 50 years now, one of the enigmas of molecular evolution has been the C-value paradox, which refers to the often massive, counterintuitive and seemingly arbitrary differences in genome size observed among eukaryotic organisms. For example, the genome of the fruitfly Drosophila melanogaster is 180 megabases (Mb), whereas that of the European brown grasshopper Podisma pedestris is 18,000 Mb. The difference in genome size of a factor of 100 is difficult to explain in view of the apparently similar levels of evolutionary, developmental and behavioural complexity of these organisms.

}, keywords = {*Genome, Animals, Chromosomes/*genetics/ultrastructure, DNA Transposable Elements/genetics, Drosophila melanogaster/*genetics, Grasshoppers/*genetics, Species Specificity}, isbn = {1471-0056 (Print)1471-0056 (Linking)}, author = {Hartl, D. L.} } @article {539036, title = {Post-genomics and the neutral theory: variation and conservation in the tumor necrosis factor-alpha promoter}, journal = {Gene}, volume = {261}, number = {1}, year = {2000}, note = {

Goldfeld, A ELeung, J YSawyer, S AHartl, D LengGM56492/GM/NIGMS NIH HHS/GM58423/GM/NIGMS NIH HHS/HL59838/HL/NHLBI NIH HHS/Research Support, U.S. Gov{\textquoteright}t, Non-P.H.S.Research Support, U.S. Gov{\textquoteright}t, P.H.S.Netherlands2001/02/13 11:00Gene. 2000 Dec 30;261(1):19-25.

}, month = {Dec 30}, pages = {19-25}, abstract = {

In the post-genomics era, molecular evolutionary geneticists have come to possess the molecular, statistical, and computational tools for estimating the relative importance of selection and random genetic drift in virtually any gene in almost any organism. We have examined single-nucleotide polymorphisms (SNPs) and nucleotide divergence across a region of approximately 1 kb in the promoter of the human tumor necrosis factor alpha (TNF-alpha) gene. TNF-alpha, which plays an important role in lymphocyte biology and in the pathogenesis of infectious and autoimmune diseases, is tightly regulated at the level of transcription through sequence-specific binding of transcription factors to cognate binding sites in a relatively small region of the 5{\textquoteright} non-coding region of the gene. Analysis of the promoter region in 207 human chromosomes revealed nine SNPs, none of which were located in regions known to be important in transcriptional activation. Comparison with one promoter sequence in each of seven species of primates revealed 162 nucleotide sites occupied by a monomorphic nucleotide in the human sample but occupied by a different nucleotide in at least one of the primate sequences (a {\textquoteright}fixed human difference{\textquoteright}). The fixed human differences were found outside the regions known to be important in transcriptional activation, and their large number suggests that they might be effectively neutral (Ns\<\<1). With regard to the human SNPs, although the hypothesis Ns approximately 0 cannot be rejected, the sample configurations suggest that the substitutions might be mildly deleterious. We emphasize the analytical insight to be gained from interspecific comparisons: through the interspecific comparisons, 3.1\% of the total sequence information yielded 94.7\% of the variable nucleotides. This combined approach, using interspecific comparisons and human polymorphism together with data from functional analyses, provides valuable insights into the evolutionary history and regulation of a key gene in the human immune response.

}, keywords = {*Evolution, Molecular, *Genomics, Animals, Binding Sites/genetics, Conserved Sequence, DNA/genetics, Genetic Variation, Genome, Human, Humans, Mutation/*genetics, Phylogeny, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, Protein Binding, Transcription Factors/metabolism, Tumor Necrosis Factor-alpha/genetics/metabolism}, isbn = {0378-1119 (Print)0378-1119 (Linking)}, author = {Goldfeld, A. E. and Leung, J. Y. and Sawyer, S. A. and Hartl, D. L.} } @article {539871, title = {Pseudogene evolution and natural selection for a compact genome}, journal = {J Hered}, volume = {91}, number = {3}, year = {2000}, note = {

Petrov, D AHartl, D Leng2000/06/01 09:00J Hered. 2000 May-Jun;91(3):221-7.

}, month = {May-Jun}, pages = {221-7}, abstract = {

Pseudogenes are nonfunctional copies of protein-coding genes that are presumed to evolve without selective constraints on their coding function. They are of considerable utility in evolutionary genetics because, in the absence of selection, different types of mutations in pseudogenes should have equal probabilities of fixation. This theoretical inference justifies the estimation of patterns of spontaneous mutation from the analysis of patterns of substitutions in pseudogenes. Although it is possible to test whether pseudogene sequences evolve without constraints for their protein-coding function, it is much more difficult to ascertain whether pseudogenes may affect fitness in ways unrelated to their nucleotide sequence. Consider the possibility that a pseudogene affects fitness merely by increasing genome size. If a larger genome is deleterious--for example, because of increased energetic costs associated with genome replication and maintenance--then deletions, which decrease the length of a pseudogene, should be selectively advantageous relative to insertions or nucleotide substitutions. In this article we examine the implications of selection for genome size relative to small (1-400 bp) deletions, in light of empirical evidence pertaining to the size distribution of deletions observed in Drosophila and mammalian pseudogenes. There is a large difference in the deletion spectra between these organisms. We argue that this difference cannot easily be attributed to selection for overall genome size, since the magnitude of selection is unlikely to be strong enough to significantly affect the probability of fixation of small deletions in Drosophila.

}, keywords = {*Evolution, Molecular, *Genome, *Selection, Genetic, Animals, DNA Transposable Elements, Drosophila/genetics, Humans, Mutagenesis, Insertional, Pseudogenes/*genetics, Sequence Deletion}, isbn = {0022-1503 (Print)0022-1503 (Linking)}, author = {Petrov, D. A. and Hartl, D. L.} } @article {539626, title = {Self-inflicted wounds, template-directed gap repair and a recombination hotspot. Effects of the mariner transposase}, journal = {Genetics}, volume = {154}, number = {2}, year = {2000}, note = {

Lohe, A RTimmons, CBeerman, ILozovskaya, E RHartl, D LengGM-33741/GM/NIGMS NIH HHS/Research Support, Non-U.S. Gov{\textquoteright}tResearch Support, U.S. Gov{\textquoteright}t, P.H.S.2000/02/03 09:00Genetics. 2000 Feb;154(2):647-56.

}, month = {Feb}, pages = {647-56}, abstract = {

Aberrant repair products of mariner transposition occur at a frequency of approximately 1/500 per target element per generation. Among 100 such mutations in the nonautonomous element peach, most had aberrations in the 5{\textquoteright} end of peach (40 alleles), in the 3{\textquoteright} end of peach (11 alleles), or a deletion of peach with or without deletion of flanking genomic DNA (29 alleles). Most mariner mutations can be explained by exonuclease "nibble" and host-mediated repair of the double-stranded gap created by the transposase, in contrast to analogous mutations in the P element. In mariner, mutations in the 5{\textquoteright} inverted repeat are smaller and more frequent than those in the 3{\textquoteright} inverted repeat, but secondary mutations in target elements with a 5{\textquoteright} lesion usually had 3{\textquoteright} lesions resembling those normally found at the 5{\textquoteright} end. We suggest that the mariner transposase distinguishes between the 5{\textquoteright} and 3{\textquoteright} ends of the element, and that the 5{\textquoteright} end is relatively more protected after strand scission. We also find: (1) that homolog-dependent gap repair is a frequent accompaniment to mariner excision, estimated as 30\% of all excision events; and (2) that mariner is a hotspot of recombination in Drosophila females, but only in the presence of functional transposase.

}, keywords = {*DNA Repair, *Recombination, Genetic, Animals, Animals, Genetically Modified, Base Sequence, DNA, Drosophila/genetics, Mutation, Templates, Genetic, Transposases/*genetics}, isbn = {0016-6731 (Print)0016-6731 (Linking)}, author = {Lohe, A. R. and Timmons, C. and Beerman, I. and Lozovskaya, E. R. and Hartl, D. L.} } @article {538691, title = {Solvent accessibility and purifying selection within proteins of Escherichia coli and Salmonella enterica}, journal = {Mol Biol Evol}, volume = {17}, number = {2}, year = {2000}, note = {

Bustamante, C DTownsend, J PHartl, D LengResearch Support, Non-U.S. Gov{\textquoteright}tResearch Support, U.S. Gov{\textquoteright}t, P.H.S.2000/03/11Mol Biol Evol. 2000 Feb;17(2):301-8.

}, month = {Feb}, pages = {301-8}, abstract = {

The neutral theory of molecular evolution predicts that variation within species is inversely related to the strength of purifying selection, but the strength of purifying selection itself must be related to physical constraints imposed by protein folding and function. In this paper, we analyzed five enzymes for which polymorphic sequence variation within Escherichia coli and/or Salmonella enterica was available, along with a protein structure. Single and multivariate logistic regression models are presented that evaluate amino acid size, physicochemical properties, solvent accessibility, and secondary structure as predictors of polymorphism. A model that contains a positive coefficient of association between polymorphism and solvent accessibility and separate intercepts for each secondary-structure element is sufficient to explain the observed variation in polymorphism between sites. The model predicts an increase in the probability of amino acid polymorphism with increasing solvent accessibility for each protein regardless of physicochemical properties, secondary-structure element, or size of the amino acid. This result, when compared with the distribution of synonymous polymorphism, which shows no association with solvent accessibility, suggests a strong decrease in purifying selection with increasing solvent accessibility.

}, keywords = {*Polymorphism, Genetic, Aldose-Ketose Isomerases/chemistry, Alkaline Phosphatase/chemistry, Bacterial Proteins/chemistry, Escherichia coli/*enzymology/genetics, Glyceraldehyde-3-Phosphate Dehydrogenases/chemistry, Likelihood Functions, Malate Dehydrogenase/chemistry, Models, Molecular, Protein Structure, Secondary, Regression Analysis, Salmonella enterica/*enzymology/genetics, Solvents}, isbn = {0737-4038 (Print)0737-4038 (Linking)}, author = {Bustamante, C. D. and Townsend, J. P. and Hartl, D. L.} } @article {538631, title = {Analysis of the type 1 pilin gene cluster fim in Salmonella: its distinct evolutionary histories in the 5{\textquoteright} and 3{\textquoteright} regions}, journal = {J Bacteriol}, volume = {181}, number = {4}, year = {1999}, note = {

Boyd, E FHartl, D LengComparative StudyResearch Support, U.S. Gov{\textquoteright}t, P.H.S.1999/02/11J Bacteriol. 1999 Feb;181(4):1301-8.

}, month = {Feb}, pages = {1301-8}, abstract = {

The type 1 pilin encoded by fim is present in both Escherichia coli and Salmonella natural isolates, but several lines of evidence indicate that similarities at the fim locus may be an example of independent acquisition rather than common ancestry. For example, the fim gene cluster is found at different chromosomal locations and with distinct gene orders in these closely related species. In this work we examined the fim gene cluster of Salmonella, the genes of which show high nucleotide sequence divergence from their E. coli counterparts, as well as a different G+C content and codon usage. DNA hybridization analysis revealed that, among the salmonellae, the fim gene cluster is present in all isolates of S. enterica but is absent from S. bongori. Molecular phylogenetic analyses of the fimA and fimI genes yield an estimate of phylogeny that is in satisfactory congruence with housekeeping and other virulence genes examined in this species. In contrast, phylogenetic analyses of the fimZ, fimY, and fimW genes indicate that horizontal transfer of this region has occurred more than once. There is also size variation in the fimZ, fimY, and fimW intergenic regions in the 3{\textquoteright} region, and these genes are absent in isolate S2983 of subspecies IIIa. Interestingly, the G+C contents of the fimZ, fimY, and fimW genes are less than 46\%, which is considerably lower than those of the other six genes of the fim cluster. This study demonstrates that horizontal transmission of all or part of the same gene cluster can occur repeatedly, with the result that different regions of a single gene cluster may have different evolutionary histories.

}, keywords = {*Evolution, Molecular, *Genes, Bacterial, *Multigene Family, Adhesins, Escherichia coli/genetics, Bacterial Outer Membrane Proteins/*genetics, Bacterial Proteins/genetics, Base Sequence, Fimbriae Proteins, Molecular Sequence Data, Nucleic Acid Hybridization, Pili, Sex/*genetics, Polymorphism, Genetic, Salmonella/*genetics/pathogenicity, Sequence Homology, Nucleic Acid}, isbn = {0021-9193 (Print)0021-9193 (Linking)}, author = {Boyd, E. F. and Hartl, D. L.} } @article {539641, title = {Genome size as a mutation-selection-drift process}, journal = {Genes Genet Syst}, volume = {74}, number = {5}, year = {1999}, note = {

Lozovskaya, E RNurminsky, D IPetrov, D AHartl, D LengGM58423/GM/NIGMS NIH HHS/Research Support, U.S. Gov{\textquoteright}t, P.H.S.JAPAN2000/03/29 09:00Genes Genet Syst. 1999 Oct;74(5):201-7.

}, month = {Oct}, pages = {201-7}, abstract = {

A novel method for estimating neutral rates and patterns of DNA evolution in Drosophila takes advantage of the propensity of non-LTR retrotransposable elements to create nonfunctional, transpositionally inactive copies as a product of transposition. For many LINE elements, most copies present in a genome at any one time are nonfunctional "dead-on-arrival" (DOA) copies. Because these are off-shoots of active, transpositionally competent "master" lineages, in a gene tree of a LINE element from multiple samples from related species, the DOA lineages are expected to map to the terminal branches and the active lineages to the internal branches, the primary exceptions being when the sample includes DOA copies that are allelic or orthologous. Analysis of nucleotide substitutions and other changes along the terminal branches therefore allows estimation of the fixation process in the DOA copies, which are unconstrained with respect to protein coding; and under selective neutrality, the fixation process estimates the underlying mutational pattern. We have studied the retroelement Helena in Drosophila. An unexpectedly high rate of DNA loss was observed, yielding a half-life of unconstrained DNA sequences approximately 60-fold faster in Drosophila than in mammals. The high rate of DNA loss suggests a straightforward explanation of the seeming paradox that Drosophila has many fewer pseudogenes than found in mammalian species. Differential rates of deletion in different taxa might also contribute to the celebrated C-value paradox of why some closely related organisms can have very different DNA contents. New data presented here rule out the possibility that the transposition process itself is highly mutagenic, hence the observed linear relation between number of deletions and number of nucleotide substitutions is most easily explained by the hypothesis that both types of changes accumulate in unconstrained sequences over time.

}, keywords = {*Evolution, Molecular, *Genome, *Retroelements, Animals, DNA, Drosophila/*genetics, Mutagenesis, Selection, Genetic}, isbn = {1341-7568 (Print)1341-7568 (Linking)}, author = {Lozovskaya, E. R. and Nurminsky, D. I. and Petrov, D. A. and Hartl, D. L.} } @article {540026, title = {Oviposition-site preference in Drosophila following interspecific gene transfer of the Alcohol dehydrogenase locus}, journal = {Behav Genet}, volume = {29}, number = {3}, year = {1999}, note = {

Siegal, M LHartl, D LengResearch Support, Non-U.S. Gov{\textquoteright}tResearch Support, U.S. Gov{\textquoteright}t, P.H.S.1999/11/05Behav Genet. 1999 May;29(3):199-204.

}, month = {May}, pages = {199-204}, abstract = {

The preference of Drosophila females to lay eggs on substrates that do or do not contain alcohol is an excellent system to study the evolutionary genetics of behavior, because (1) there is variation in this behavior within and among species, (2) the behavior is amenable to laboratory investigation, and (3) the behavior presumably has a direct relationship to reproductive fitness. Moreover, a key genetic component of the system, the Alcohol dehydrogenase (Adh) locus, is arguably the most well characterized gene known. However, because the Adh gene and its genetic background are inseparable in reproductively isolated species, it is difficult to establish its role in behavioral divergence. By transgene coplacement, we created pairs of strains of D. melanogaster expressing an Adh allele from either D. melanogaster or D. affinidisjuncta, a Hawaiian species with very low levels of ADH in adults. When raised on ethanol-containing medium, the affinidisjuncta-Adh strains experience high mortality relative to the melanogaster-Adh strains. However, affinidisjuncta-Adh females show the same preference for oviposition on ethanol-containing medium as melanogaster-Adh females. Thus, preference for ethanol in these strains is not determined primarily by Adh genotype.

}, keywords = {*Gene Transfer Techniques, Alcohol Dehydrogenase/*genetics, Animals, Chromosome Mapping, Drosophila/*genetics, Female, Oviposition/*genetics, Species Specificity}, isbn = {0001-8244 (Print)0001-8244 (Linking)}, author = {Siegal, M. L. and Hartl, D. L.} } @article {539866, title = {Patterns of nucleotide substitution in Drosophila and mammalian genomes}, journal = {Proc Natl Acad Sci U S A}, volume = {96}, number = {4}, year = {1999}, note = {

Petrov, D AHartl, D LengHG01250/HG/NHGRI NIH HHS/Research Support, Non-U.S. Gov{\textquoteright}tResearch Support, U.S. Gov{\textquoteright}t, P.H.S.1999/02/17Proc Natl Acad Sci U S A. 1999 Feb 16;96(4):1475-9.

}, month = {Feb 16}, pages = {1475-9}, abstract = {

To estimate patterns of molecular evolution of unconstrained DNA sequences, we used maximum parsimony to separate phylogenetic trees of a non-long terminal repeat retrotransposable element into either internal branches, representing mainly the constrained evolution of active lineages, or into terminal branches, representing mainly nonfunctional "dead-on-arrival" copies that are unconstrained by selection and evolve as pseudogenes. The pattern of nucleotide substitutions in unconstrained sequences is expected to be congruent with the pattern of point mutation. We examined the retrotransposon Helena in the Drosophila virilis species group (subgenus Drosophila) and the Drosophila melanogaster species subgroup (subgenus Sophophora). The patterns of point mutation are indistinguishable, suggesting considerable stability over evolutionary time (40-60 million years). The relative frequencies of different point mutations are unequal, but the "transition bias" results largely from an approximately 2-fold excess of G.C to A.T substitutions. Spontaneous mutation is biased toward A.T base pairs, with an expected mutational equilibrium of approximately 65\% A + T (quite similar to that of long introns). These data also enable the first detailed comparison of patterns of point mutations in Drosophila and mammals. Although the patterns are different, all of the statistical significance comes from a much greater rate of G.C to A.T substitution in mammals, probably because of methylated cytosine "hotspots." When the G.C to A.T substitutions are discounted, the remaining differences are considerably reduced and not statistically significant.

}, keywords = {*Evolution, Molecular, *Genome, *Phylogeny, *Point Mutation, *Retroelements, Animals, Base Pairing, Codon, Drosophila melanogaster/genetics, Drosophila/*genetics, Mammals/*genetics}, isbn = {0027-8424 (Print)0027-8424 (Linking)}, author = {Petrov, D. A. and Hartl, D. L.} } @article {538881, title = {Regulatory potential of nonautonomous mariner elements and subfamily crosstalk}, journal = {Genetica}, volume = {107}, number = {1-3}, year = {1999}, note = {

De Aguiar, DHartl, D LengResearch Support, Non-U.S. Gov{\textquoteright}tResearch Support, U.S. Gov{\textquoteright}t, Non-P.H.S.Research Support, U.S. Gov{\textquoteright}t, P.H.S.NETHERLANDS2000/08/22 11:00Genetica. 1999;107(1-3):79-85.

}, pages = {79-85}, abstract = {

Two naturally occurring nonautonomous mariner elements were tested in vivo for their ability to down-regulate excision of a target element in the presence of functional mariner transposase. The tested elements were the peach element isolated from Drosophila mauritiana, which encodes a transposase that differs from the autonomous element Mos1 in four amino acid replacements, and the DTBZ1 element isolated from D. teissieri, which encodes a truncated protein consisting of the first 132 residues at the amino end of the normally 345-residue transposase. We provide evidence that the protein from the peach element does interact to down-regulate wildtype transposase, indicating that at least some nonautonomous elements in natural populations that retain their open reading frame may play a regulatory role. In contrast, our tests reveal at most a weak interaction between transposase from the autonomous Mos1 element and the truncated protein from DTBZ1, and none between Mos1 transposase and that from the distantly related mariner-like element Himar1 identified in the horn fly Haematobia irritans. Hence, the extent of regulatory crosstalk between mariner-like elements may be limited to closely related ones. The evolutionary implications of these results are discussed.

}, keywords = {*DNA Transposable Elements, Animals, DNA-Binding Proteins/*genetics, Drosophila/*genetics, Evolution, Molecular, Regulatory Sequences, Nucleic Acid, Transposases/genetics}, isbn = {0016-6707 (Print)0016-6707 (Linking)}, author = {De Aguiar, D. and Hartl, D. L.} } @article {538626, title = {Chromosomal regions specific to pathogenic isolates of Escherichia coli have a phylogenetically clustered distribution}, journal = {J Bacteriol}, volume = {180}, number = {5}, year = {1998}, note = {

Boyd, E FHartl, D LengGM322/GM/NIGMS NIH HHS/Research Support, U.S. Gov{\textquoteright}t, P.H.S.1998/03/12J Bacteriol. 1998 Mar;180(5):1159-65.

}, month = {Mar}, pages = {1159-65}, abstract = {

We studied the ancestry of virulence-associated genes in Escherichia coli by examining chromosomal regions specific to pathogenic isolates. The four virulence determinants examined were the alpha-hemolysin (hly) loci hlyI and hlyII, the type II capsule gene cluster kps, and the P (pap) and S (sfa) fimbria gene clusters. All four loci were shown previously to be associated with pathogenicity islands of uropathogenic E. coli isolates. The hly, kps, sfa, and pap regions each have an unexpected clustered distribution among the E. coli collection of reference (ECOR) strains, but all these regions were absent from a collection of diarrheagenic E. coli isolates. Strains in the ECOR subgroup B2 typically had a combination of at least three of the four loci, and all strains in subgroup D had a copy of the kps and pap clusters. In contrast, only four strains in subgroup A had either hly, kps, sfa, or pap, and no subgroup A strains had all four together. Strains of subgroup B1 were devoid of all four virulence regions, with the exception of one isolate that had a copy of the sfa gene cluster. This phylogenetic distribution of strain-specific sequences corresponds to the ECOR groups with the largest genome size, namely, B2 and D. We propose that the pathogenicity islands are ancestral to subgroups B2 and D and were acquired after speciation, with subsequent horizontal transfer into some group A, B1, and E lineages. These results suggest that the hly, kps, sfa, and pap pathogenicity determinants may play a role in the evolution of enteric bacteria quite apart from, and perhaps with precedence over, their ability to cause disease.

}, keywords = {*Escherichia coli Proteins, *Genes, Bacterial, *Periplasmic Proteins, Adhesins, Bacterial/genetics, Animals, Bacterial Capsules/genetics, Bacterial Proteins/genetics, Bacterial Toxins/genetics, Base Sequence, Biological Evolution, Chromosomes, Bacterial/*genetics, Escherichia coli/classification/*genetics/*pathogenicity, Fimbriae, Bacterial/genetics, Genetic Variation, Hemolysin Proteins/genetics, Humans, Molecular Sequence Data, Operon, Phylogeny, Polymorphism, Genetic, Virulence/*genetics}, isbn = {0021-9193 (Print)0021-9193 (Linking)}, author = {Boyd, E. F. and Hartl, D. L.} } @article {539791, title = {Cytoplasmic dynein intermediate-chain isoforms with different targeting properties created by tissue-specific alternative splicing}, journal = {Mol Cell Biol}, volume = {18}, number = {11}, year = {1998}, note = {

Nurminsky, D INurminskaya, M VBenevolenskaya, E VShevelyov, Y YHartl, D LGvozdev, V AengResearch Support, Non-U.S. Gov{\textquoteright}t1998/10/17Mol Cell Biol. 1998 Nov;18(11):6816-25.

}, month = {Nov}, pages = {6816-25}, abstract = {

The intermediate chains (ICs) are the subunits of the cytoplasmic dynein that provide binding of the complex to cargo organelles through interaction of their N termini with dynactin. We present evidence that in Drosophila, the IC subunits are represented by at least 10 structural isoforms, created by the alternative splicing of transcripts from a unique Cdic gene. The splicing pattern is tissue specific. A constitutive set of four IC isoforms is expressed in all tissues tested; in addition, tissue-specific isoforms are found in the ovaries and nervous tissue. The structural variations between isoforms are limited to the N terminus of the IC molecule, where the interaction with dynactin takes place. This suggests differences in the dynactin-mediated organelle binding by IC isoforms. Accordingly, when transiently expressed in Drosophila Schneider-3 cells, the IC isoforms differ in their intracellular targeting properties from each other. A mechanism is proposed for the regulation of dynein binding to organelles through the changes in the content of the IC isoform pool.

}, keywords = {*Drosophila Proteins, Alternative Splicing, Amino Acid Sequence, Animals, Base Sequence, Cell Line, Cloning, Molecular, Drosophila/*metabolism, Dyneins/*chemistry, Exons/genetics, Insect Proteins/*chemistry, Introns/genetics, Microscopy, Fluorescence, Microtubule-Associated Proteins/*metabolism, Molecular Sequence Data, RNA, Messenger/metabolism, Sequence Analysis, DNA, Sequence Homology, Amino Acid}, isbn = {0270-7306 (Print)0270-7306 (Linking)}, author = {Nurminsky, D. I. and Nurminskaya, M. V. and Benevolenskaya, E. V. and Shevelyov, Y. Y. and Hartl, D. L. and Gvozdev, V. A.} } @article {538616, title = {Diversifying selection governs sequence polymorphism in the major adhesin proteins fimA, papA, and sfaA of Escherichia coli}, journal = {J Mol Evol}, volume = {47}, number = {3}, year = {1998}, note = {

Boyd, E FHartl, D LengResearch Support, U.S. Gov{\textquoteright}t, P.H.S.1998/09/11J Mol Evol. 1998 Sep;47(3):258-67.

}, month = {Sep}, pages = {258-67}, abstract = {

Fimbriae or pili are essential adherence factors usually found in pathogenic bacteria to aid colonization of host cells. Three major structural pilin genes, fimA, sfaA, and papA, from Escherichia coli natural isolates were examined and nucleotide sequence data revealed elevated levels of both synonymous and nonsynonymous site variation at these loci. Examination of synonymous site variation shows a fivefold increase in fimA sites, relative to the housekeeping gene mdh; and similarly the sfaA and papA genes have increased synonymous sites variation relative to fimA. Nonsynonymous site variation is also elevated at all three loci but, in particular, at the papA locus (kN = 0.44). The kN/kS ratio for the three genes are among the highest yet reported for E. coli genes. Regional variation in nucleotide polymorphism within each of the genes reveal hypervariable segments where nonsynonymous substitutions exceed synonymous substitutions. We propose that at the fimA, papA, and sfaA genes, diversifying selection has brought about the increase levels of polymorphism.

}, keywords = {*Escherichia coli Proteins, *Fimbriae Proteins, *Polymorphism, Genetic, Adhesins, Escherichia coli/*genetics, Bacterial Proteins/*genetics, Base Composition, Base Sequence, Codon, DNA, Bacterial/analysis, Escherichia coli/*genetics, Evolution, Molecular, Molecular Sequence Data, Phylogeny, Polymerase Chain Reaction/methods, Selection, Genetic, Sequence Analysis, DNA}, isbn = {0022-2844 (Print)0022-2844 (Linking)}, author = {Boyd, E. F. and Hartl, D. L.} } @article {540021, title = {An experimental test for lineage-specific position effects on alcohol dehydrogenase (Adh) genes in Drosophila}, journal = {Proc Natl Acad Sci U S A}, volume = {95}, number = {26}, year = {1998}, note = {

Siegal, M LHartl, D LengGM-33741/GM/NIGMS NIH HHS/HG-01250/HG/NHGRI NIH HHS/Comparative StudyResearch Support, U.S. Gov{\textquoteright}t, P.H.S.1998/12/23Proc Natl Acad Sci U S A. 1998 Dec 22;95(26):15513-8.

}, month = {Dec 22}, pages = {15513-8}, abstract = {

Independent transgene insertions differ in expression based on their location in the genome; these position effects are of interest because they reflect the influence of genome organization on gene regulation. Position effects also represent potentially insurmountable obstacles to the rigorous functional comparison of homologous genes from different species because (i) quantitative variation in expression of each gene across genomic positions (generalized position effects, or GPEs) may overwhelm differences between the genes of interest, or (ii) divergent genes may be differentially sensitive to position effects, reflecting unique interactions between each gene and its genomic milieu (lineage-specific position effects, or LSPEs). We have investigated both types of position-effect variation by applying our method of transgene coplacement, which allows comparisons of transgenes in the same position in the genome of Drosophila melanogaster. Here we report an experimental test for LSPE in Drosophila. The alcohol dehydrogenase (Adh) genes of D. melanogaster and Drosophila affinidisjuncta differ in both tissue distribution and amounts of ADH activity. Despite this striking regulatory divergence, we found a very high correlation in overall ADH activity between the genes of the two species when placed in the same genomic position as assayed in otherwise Adh-null adults and larvae. These results argue against the influence of LSPE for these sequences, although the effects of GPE are significant. Our new findings validate the coplacement approach and show that it greatly magnifies the power to detect differences in expression between transgenes. Transgene coplacement thus dramatically extends the range of functional and evolutionary questions that can be addressed by transgenic technology.

}, keywords = {Alcohol Dehydrogenase/*genetics/metabolism, Animals, Animals, Genetically Modified, Drosophila melanogaster/enzymology/*genetics, Drosophila/enzymology/*genetics, Female, Gene Expression Regulation, Enzymologic, Larva, Male, Plasmids, Sex Characteristics, Species Specificity, Transcription, Genetic}, isbn = {0027-8424 (Print)0027-8424 (Linking)}, author = {Siegal, M. L. and Hartl, D. L.} } @article {540121, title = {Factors contributing to the hybrid dysgenesis syndrome in Drosophila virilis}, journal = {Genet Res}, volume = {71}, number = {2}, year = {1998}, note = {

Vieira, JVieira, C PHartl, D LLozovskaya, E RengHG-01250/HG/NHGRI NIH HHS/Research Support, Non-U.S. Gov{\textquoteright}tResearch Support, U.S. Gov{\textquoteright}t, P.H.S.ENGLAND1998/08/26Genet Res. 1998 Apr;71(2):109-17.

}, month = {Apr}, pages = {109-17}, abstract = {

A hybrid dysgenesis syndrome in Drosophila virilis is associated with the mobilization of at least four unrelated transposable elements designated Helena, Paris, Penelope and Ulysses. We carried out 42 crosses between eight strains differing in transposable element copy number in order to assess their contributions to hybrid dysgenesis. Linear regression and stepwise regression analysis was performed to estimate the correlation between the difference in euchromatic transposable element number between the parental flies of different strains involved in the crosses and the percentage, in the progeny of these crosses, of males with atrophic gonads. Male gonadal atrophy is a typical manifestation of the D. virilis hybrid dysgenesis syndrome. About half the variability in the level of male gonadal atrophy can be attributed to Penelope and Paris/Helena. Other factors also seem to play a significant role in hybrid dysgenesis in D. virilis, including maternally transmitted host factors and/or uncontrolled environmental variation. In the course of this work a novel transposable element named Telemac was found. Telemac is also mobilized in hybrid dysgenesis but does not appear to play a major causative role.

}, keywords = {*DNA Transposable Elements, Animals, Base Sequence, DNA Primers, Drosophila/*genetics, Gonadal Dysgenesis/*genetics, Male}, isbn = {0016-6723 (Linking)}, author = {Vieira, J. and Vieira, C. P. and Hartl, D. L. and Lozovskaya, E. R.} } @article {539736, title = {Genome size and intron size in Drosophila}, journal = {Mol Biol Evol}, volume = {15}, number = {6}, year = {1998}, note = {

Moriyama, E NPetrov, D AHartl, D LengGM33741/GM/NIGMS NIH HHS/HG01250/HG/NHGRI NIH HHS/Comparative StudyLetterResearch Support, U.S. Gov{\textquoteright}t, P.H.S.1998/06/06Mol Biol Evol. 1998 Jun;15(6):770-3.

}, month = {Jun}, pages = {770-3}, keywords = {*Evolution, Molecular, *Genes, Insect, *Genome, Animals, DNA/genetics, Drosophila melanogaster/genetics, Drosophila/classification/*genetics, Introns/*genetics, Pseudogenes/genetics, Retroelements/*genetics, Sequence Deletion, Sequence Homology, Nucleic Acid, Species Specificity}, isbn = {0737-4038 (Print)0737-4038 (Linking)}, author = {Moriyama, E. N. and Petrov, D. A. and Hartl, D. L.} } @article {539861, title = {High rate of DNA loss in the Drosophila melanogaster and Drosophila virilis species groups}, journal = {Mol Biol Evol}, volume = {15}, number = {3}, year = {1998}, note = {

Petrov, D AHartl, D LengGM33741/GM/NIGMS NIH HHS/HG01250/HG/NHGRI NIH HHS/Research Support, U.S. Gov{\textquoteright}t, P.H.S.1998/03/21Mol Biol Evol. 1998 Mar;15(3):293-302.

}, month = {Mar}, pages = {293-302}, abstract = {

We recently proposed that patterns of evolution of non-LTR retrotransposable elements can be used to study patterns of spontaneous mutation. Transposition of non-LTR retrotransposable elements commonly results in creation of 5{\textquoteright} truncated, "dead-on-arrival" copies. These inactive copies are effectively pseudogenes and, according to the neutral theory, their molecular evolution ought to reflect rates and patterns of spontaneous mutation. Maximum parsimony can be used to separate the evolution of active lineages of a non-LTR element from the fate of the "dead-on-arrival" insertions and to directly assess the relative frequencies of different types of spontaneous mutations. We applied this approach using a non-LTR element, Helena, in the Drosophila virilis group and have demonstrated a surprisingly high incidence of large deletions and the virtual absence of insertions. Based on these results, we suggested that Drosophila in general may exhibit a high rate of spontaneous large deletions and have hypothesized that such a high rate of DNA loss may help to explain the puzzling dearth of bona fide pseudogenes in Drosophila. We also speculated that variation in the rate of spontaneous deletion may contribute to the divergence of genome size in different taxa by affecting the amount of superfluous "junk" DNA such as, for example, pseudogenes or long introns. In this paper, we extend our analysis to the D. melanogaster subgroup, which last shared a common ancestor with the D. virilis group approximately 40 MYA. In a different region of the same transposable element, Helena, we demonstrate that inactive copies accumulate deletions in species of the D. melanogaster subgroup at a rate very similar to that of the D. virilis group. These results strongly suggest that the high rate of DNA loss is a general feature of Drosophila and not a peculiar property of a particular stretch of DNA in a particular species group.

}, keywords = {*Evolution, Molecular, Animals, DNA/*genetics, Drosophila melanogaster/*genetics, Drosophila/*genetics, Molecular Sequence Data, Mutagenesis, Phylogeny, Pseudogenes/genetics, Retroelements/genetics, Sequence Alignment, Sequence Analysis, DNA, Sequence Deletion/genetics}, isbn = {0737-4038 (Print)0737-4038 (Linking)}, author = {Petrov, D. A. and Hartl, D. L.} } @article {539851, title = {Pseudogene evolution in Drosophila suggests a high rate of DNA loss}, journal = {Mol Biol Evol}, volume = {15}, number = {11}, year = {1998}, note = {

Petrov, D AChao, Y CStephenson, E CHartl, D LengGM33741/GM/NIGMS NIH HHS/HG01250/HG/NHGRI NIH HHS/LetterResearch Support, Non-U.S. Gov{\textquoteright}tResearch Support, U.S. Gov{\textquoteright}t, Non-P.H.S.Research Support, U.S. Gov{\textquoteright}t, P.H.S.2003/02/08 04:00Mol Biol Evol. 1998 Nov;15(11):1562-7.

}, month = {Nov}, pages = {1562-7}, keywords = {*Evolution, Molecular, *Gene Deletion, Animals, Base Sequence, Drosophila melanogaster/genetics, Drosophila/*genetics, Molecular Sequence Data, Pseudogenes/*genetics}, isbn = {0737-4038 (Print)0737-4038 (Linking)}, author = {Petrov, D. A. and Chao, Y. C. and Stephenson, E. C. and Hartl, D. L.} } @article {538621, title = {Salmonella virulence plasmid. Modular acquisition of the spv virulence region by an F-plasmid in Salmonella enterica subspecies I and insertion into the chromosome of subspecies II, IIIa, IV and VII isolates}, journal = {Genetics}, volume = {149}, number = {3}, year = {1998}, note = {

Boyd, E FHartl, D LengGM-40322/GM/NIGMS NIH HHS/Research Support, U.S. Gov{\textquoteright}t, P.H.S.1998/07/03Genetics. 1998 Jul;149(3):1183-90.

}, month = {Jul}, pages = {1183-90}, abstract = {

The spv operon is common to all Salmonella virulence plasmids. DNA hybridization analysis indicates that the spv region is limited in distribution to serovars of Salmonella enterica subspecies I, II, IIIa, IV, and VII and is absent from Salmonella bongori isolates. Among strains of subspecies II, IIIa, and VII, all isolates examined contained sequences that hybridized with the spv region. However, among isolates of subspecies I, DNA sequences capable of hybridizing with the spv region were found in some isolates of certain serovars. Furthermore, in isolates of subspecies I, the virulence plasmid was found in the same set of isolates as an F-related plasmid, as determined by the presence of the spv region of the virulence plasmid and the finO, traD, and repA sequences of the F-plasmid. The concordance of the virulence plasmid and all three F-plasmid sequences in subspecies I serovar Choleraesuis, Paratyphi, and Typhimurium is most easily explained if the spv region is carried in an F-related plasmid in these isolates. In contrast, among S. enterica subspecies II, IIIa, IV, and VII, the isolates that contain spv sequences did not hybridize with an F-related plasmid or any other identifiable plasmid. With the use of pulse-field gel electrophoresis, the spv region in subspecies II, IIIa, and VII was found to be encoded on the chromosome. Analysis of the phylogenetic distribution of spv among Salmonella isolates and comparative nucleotide sequence analysis of spvA and spvC suggests that the spv region was acquired very recently, after speciation of the salmonellae.

}, keywords = {*Chromosomes, Bacterial, *F Factor, Base Sequence, Mutagenesis, Insertional, Operon, Phylogeny, Polymerase Chain Reaction, Polymorphism, Genetic, Salmonella enterica/classification/*genetics/*pathogenicity, Salmonella enteritidis/genetics, Salmonella paratyphi A/genetics, Salmonella typhimurium/genetics, Sequence Alignment, Sequence Deletion, Sequence Homology, Nucleic Acid, Virulence/genetics}, isbn = {0016-6731 (Print)0016-6731 (Linking)}, author = {Boyd, E. F. and Hartl, D. L.} } @article {539796, title = {Selective sweep of a newly evolved sperm-specific gene in Drosophila}, journal = {Nature}, volume = {396}, number = {6711}, year = {1998}, note = {

Nurminsky, D INurminskaya, M VDe Aguiar, DHartl, D LengResearch Support, U.S. Gov{\textquoteright}t, P.H.S.ENGLAND1998/12/22 03:04Nature. 1998 Dec 10;396(6711):572-5.

}, month = {Dec 10}, pages = {572-5}, abstract = {

The pattern of genetic variation across the genome of Drosophila melanogaster is consistent with the occurrence of frequent {\textquoteright}selective sweeps{\textquoteright}, in which new favourable mutations become incorporated into the species so quickly that linked alleles can {\textquoteright}hitchhike{\textquoteright} and also become fixed. Because of the hitchhiking of linked genes, it is generally difficult to identify the target of any putative selective sweep. Here, however, we identify a new gene in D. melanogaster that codes for a sperm-specific axonemal dynein subunit. The gene has a new testes-specific promoter derived from a protein-coding region in a gene encoding the cell-adhesion protein annexin X (AnnX), and it contains a new protein-coding exon derived from an intron in a gene encoding a cytoplasmic dynein intermediate chain (Cdic). The new transcription unit, designated Sdic (for sperm-specific dynein intermediate chain), has been duplicated about tenfold in a tandem array. Consistent with the selective sweep of this gene, the level of genetic polymorphism near Sdic is unusually low. The discovery of this gene supports other results that point to the rapid molecular evolution of male reproductive functions.

}, keywords = {*Drosophila Proteins, *Evolution, Molecular, *Spermatozoa/metabolism, Amino Acid Sequence, Animals, Animals, Genetically Modified, Annexins/genetics, Artificial Gene Fusion, Axonemal Dyneins, Base Sequence, DNA, Drosophila melanogaster/*genetics, Dyneins/*genetics, Gene Expression Regulation, Genes, Insect, Insect Proteins/*genetics, Male, Molecular Sequence Data, Promoter Regions, Genetic, Recombinant Fusion Proteins/genetics, Selection, Genetic, Sequence Deletion, Testis/metabolism}, isbn = {0028-0836 (Print)0028-0836 (Linking)}, author = {Nurminsky, D. I. and Nurminskaya, M. V. and De Aguiar, D. and Hartl, D. L.} } @article {539376, title = {Towards a theory of evolutionary adaptation}, journal = {Genetica}, volume = {102-103}, number = {1-6}, year = {1998}, note = {

Hartl, D LTaubes, C HengResearch Support, U.S. Gov{\textquoteright}t, Non-P.H.S.Research Support, U.S. Gov{\textquoteright}t, P.H.S.NETHERLANDS1998/08/28Genetica. 1998;102-103(1-6):525-33.

}, pages = {525-33}, abstract = {

Most theoretical models in population genetics fail to deal in a realistic manner with the process of mutation. They are consequently not informative about the central evolutionary problem of the origin, progression, and limit of adaptation. Here we present an explicit distribution of phenotypes expected in an ensemble of populations under a mutation-selection-drift model that allows mutations with a distribution of adaptive values to occur randomly in time. The model of mutation is a geometrical model in which the effect of a new mutation is determined by a random angle in n dimensional space and in which the adaptive value (fitness) of an organism decreases as the square of the deviation of its phenotype from an optimum. Each new mutation is subjected to random genetic drift and fixed or lost according to its selective value and the effective population number. Time is measured in number of fixation events, so that, at any point in time, each population is regarded as genetically homogeneous. In this mutation-selection-drift model, among an ensemble of populations, the equilibrium average phenotype coincides with the optimum because the distribution of positive and negative deviations from the optimum is symmetrical. However, at equilibrium the mean of the absolute value of the deviation from the optimum equals square root of n-/8Ns), where n is the dimensionality of the trait space, N is the effective population size, and s is the selection coefficient against a mutation whose phenotype deviates by one unit from the optimum. Furthermore, at equilibrium, the average fitness across the ensemble of populations equals 1 - (n + 1)/8N. When n is sufficiently large, there is a strong mutation pressure toward the fixation of slightly deleterious mutations. This feature relates our model to the nearly neutral theory of molecular evolution.

}, keywords = {*Biological Evolution, *Models, Genetic, *Selection, Genetic, Adaptation, Physiological/*genetics, Evolution, Molecular, Mathematical Computing, Phenotype}, isbn = {0016-6707 (Print)0016-6707 (Linking)}, author = {Hartl, D. L. and Taubes, C. H.} } @article {538976, title = {Transposition of the mariner element from Drosophila mauritiana in zebrafish}, journal = {Proc Natl Acad Sci U S A}, volume = {95}, number = {9}, year = {1998}, note = {

Fadool, J MHartl, D LDowling, J EengEY00811/EY/NEI NIH HHS/EY06554/EY/NEI NIH HHS/EY11774/EY/NEI NIH HHS/Research Support, U.S. Gov{\textquoteright}t, P.H.S.1998/06/06Proc Natl Acad Sci U S A. 1998 Apr 28;95(9):5182-6.

}, month = {Apr 28}, pages = {5182-6}, abstract = {

With the increased popularity of zebrafish (Danio rerio) for mutagenesis studies, efficient methods for manipulation of its genome are needed. One approach is the use of a transposable element as a vector for gene transfer in this species. We report here the transformation of zebrafish and germ-line transmission of the mariner element from Drosophila mauritiana. The mariner element was selected because its transposition is independent of host-specific factors. One- to two-cell-stage zebrafish embryos were coinjected with a supercoiled plasmid carrying the nonautonomous mariner element peach and mRNA encoding the transposase. Surviving larvae were reared to adulthood, and the transmission of peach to the F1 generation was tested by PCR. Four of the 12 founders, following plasmid injections on 2 different days, transmitted the element to their progeny. Inheritance of the transgene from the F1 to the F2 generation showed a Mendelian pattern. No plasmid sequences were detected by PCR or Southern blot analysis, indicating transposition of peach rather than random integration of the plasmid DNA. These data provide evidence of transformation of a vertebrate with a transposable element and support the host-independent mechanism for transposition of the mariner element. We suggest this system could be used for insertional mutagenesis or for identifying active regions of the genome in the zebrafish.

}, keywords = {*DNA Transposable Elements, Animals, Animals, Inbred Strains, Drosophila/*genetics, Genetic Engineering/methods, Genetic Vectors, Transposases/genetics, Zebrafish/*genetics}, isbn = {0027-8424 (Print)0027-8424 (Linking)}, author = {Fadool, J. M. and Hartl, D. L. and Dowling, J. E.} } @article {540111, title = {Discordant rates of chromosome evolution in the Drosophila virilis species group}, journal = {Genetics}, volume = {147}, number = {1}, year = {1997}, note = {

Vieira, JVieira, C PHartl, D LLozovskaya, E RengHG-01250/HG/NHGRI NIH HHS/Comparative StudyResearch Support, Non-U.S. Gov{\textquoteright}tResearch Support, U.S. Gov{\textquoteright}t, P.H.S.1997/09/01Genetics. 1997 Sep;147(1):223-30.

}, month = {Sep}, pages = {223-30}, abstract = {

In Drosophila, the availability of polytene chromosome maps and of sets of probes covering most regions of the chromosomes allows a direct comparison of the organization of the genome in different species. In this work, we report the localization, in Drosophila virilis, D. montana, and D. novamexicana, of \> 100 bacteriophage PI clones containing approximately 65 kilobase inserts of genomic DNA from D. virilis. Each clone hybridizes with a single euchromatic site in either chromosome 1 or chromosome 3 in D. virilis. From these data, it is possible to estimate the minimum number of inversions required to transform the map positions of the probes in one species into the map positions of the same probes in a related species. The data indicate that, in the D. virilis species group, the X chromosome has up to four times the number of inversions as are observed in chromosome 3. The first photographic polytene chromosome maps for D. montana and D. novamexicana are also presented.

}, keywords = {*Biological Evolution, *Chromosomes, Animals, Chromosome Inversion, Chromosome Mapping, Drosophila/*cytology}, isbn = {0016-6731 (Print)0016-6731 (Linking)}, author = {Vieira, J. and Vieira, C. P. and Hartl, D. L. and Lozovskaya, E. R.} } @article {540106, title = {The evolution of small gene clusters: evidence for an independent origin of the maltase gene cluster in Drosophila virilis and Drosophila melanogaster}, journal = {Mol Biol Evol}, volume = {14}, number = {10}, year = {1997}, note = {

Vieira, C PVieira, JHartl, D LengHG01250/HG/NHGRI NIH HHS/Research Support, Non-U.S. Gov{\textquoteright}tResearch Support, U.S. Gov{\textquoteright}t, P.H.S.1997/10/23Mol Biol Evol. 1997 Oct;14(10):985-93.

}, month = {Oct}, pages = {985-93}, abstract = {

We analyzed a 5,770-bp genomic region of Drosophila virilis that contains a cluster of two maltase genes showing sequence similarity with genes in a cluster of three maltase genes previously identified in Drosophila melanogaster. The D. virilis maltase genes are designated Mav1 and Mav2. In addition to being different in gene number, the cluster of genes in D. virilis differs dramatically in intron-exon structure from the maltase genes in D. melanogaster, the transcriptional orientation of the genes in the cluster also differs between the species. Our findings support a model in which the maltase gene cluster in D. virilis and D. melanogaster evolved independently. Furthermore, while in D. melanogaster the maltase gene cluster lies only 10 kb distant from the larval cuticle gene cluster, the maltase and larval cuticle gene clusters in D. virilis are located very far apart and on a different chromosome than that expected from the known chromosome arm homologies between D. virilis and D. melanogaster. A region of the genome containing the maltase and larval cuticle gene clusters appears to have been relocated between nonhomologous chromosomes.

}, keywords = {*Evolution, Molecular, *Genes, Insect, *Multigene Family, Aedes/genetics, alpha-Glucosidases/biosynthesis/chemistry/*genetics, Amino Acid Sequence, Animals, Anopheles/genetics, Base Sequence, Conserved Sequence, Drosophila melanogaster/enzymology/*genetics, Drosophila/enzymology/*genetics, Gene Library, Molecular Sequence Data, Polymerase Chain Reaction, Restriction Mapping, Sequence Alignment, Sequence Homology, Amino Acid}, isbn = {0737-4038 (Print)0737-4038 (Linking)}, author = {Vieira, C. P. and Vieira, J. and Hartl, D. L.} } @article {540116, title = {A framework physical map of Drosophila virilis based on P1 clones: applications in genome evolution}, journal = {Chromosoma}, volume = {106}, number = {2}, year = {1997}, note = {

Vieira, JVieira, C PHartl, D LLozovskaya, E RengComparative StudyResearch Support, Non-U.S. Gov{\textquoteright}tResearch Support, U.S. Gov{\textquoteright}t, P.H.S.GERMANY1997/07/01Chromosoma. 1997 Jul;106(2):99-107.

}, month = {Jul}, pages = {99-107}, abstract = {

The analysis of patterns of genome evolution may help to evaluate the evolutionary forces that shape the composition and organization of the genome. Comparisons between the physical maps of divergent species can be used to identify conserved blocks of closely linked genes whose synteny is possibly under selective constraint. We have used in situ hybridization to determine the genomic position of 732 randomly selected clones from a bacteriophage P1 library of Drosophila virilis. The resulting map includes at least one clone in each of 69\% of the subdivisions into which the D. virilis polytene chromosomes are divided. A subset of these clones was used to carry out a comparative physical analysis of chromosome 2 from D. virilis and from Drosophila montana. A number of discrepancies with the classical scenario of chromosome evolution were noted. The D. virilis P1 clones were also used to determine the physical relations between ten genes that are located in the X chromosome of Drosophila melanogaster between the markers crn (2F1) and omb (4C5-6). In this region, which is approximately 2 Mb in length, there have been at least six breakpoints since the divergence of the species, and six of the genes are found at widely scattered locations in the D. virilis X chromosome. However, a block of four functionally unrelated genes, including white, roughest, Notch, and dunce, seems to be conserved between the two species.

}, keywords = {*Biological Evolution, *Chromosome Mapping, *Genome, Animals, Bacteriophage P1/genetics, Drosophila/*genetics, Genes, Insect, Genomic Library, Species Specificity}, isbn = {0009-5915 (Print)0009-5915 (Linking)}, author = {Vieira, J. and Vieira, C. P. and Hartl, D. L. and Lozovskaya, E. R.} } @article {539921, title = {Heterogeneity of the internal transcribed spacer (ITS-2) region within individual deer ticks}, journal = {Insect Mol Biol}, volume = {6}, number = {2}, year = {1997}, note = {

Rich, S MRosenthal, B MTelford, S R 3rdSpielman, AHartl, D LAyala, F JengENGLAND1997/05/01Insect Mol Biol. 1997 May;6(2):123-9.

}, month = {May}, pages = {123-9}, abstract = {

To determine whether nuclear rDNA sequences provide a useful means for assessing the structure of populations of Ixodes ticks, we compared variability among copies of an internal transcribed spacer (ITS-2) sequence within individual ticks to the variability between ticks. At least 4\% of the nucleotides comprising this sequence vary among the copies present within individual ticks. ITS-2 diversity in each of two ticks is nearly half as great as that reported between ticks from geographically disparate populations. Because individual ticks retain ancestral polymorphism, ITS-2 variation does not accurately reflect descent relationships among these ticks. Sequencing single copies of PCR-amplified ITS-2 therefore does not permit assessment of the phylogenetic relationships among the I. ricinus-like ticks in eastern North America. We recommend caution in future analyses, and emphasize the importance of procedures designed to ensure that the many paralogous copies of the rDNA cistron have been sufficiently homogenized by concerted evolutionary processes. Such precautionary measures will make certain that phylogenetic trees based on these gene sequences reflect the phyletic relatedness of the biological species.

}, keywords = {*DNA, Ribosomal, *Genetic Heterogeneity, Animals, Base Sequence, Deer/parasitology, DNA, Ixodes/classification/*genetics, Molecular Sequence Data}, isbn = {0962-1075 (Print)0962-1075 (Linking)}, author = {Rich, S. M. and Rosenthal, B. M. and Telford, S. R., 3rd and Spielman, A. and Hartl, D. L. and Ayala, F. J.} } @article {539186, title = {Mariner sails into Leishmania}, journal = {Science}, volume = {276}, number = {5319}, year = {1997}, note = {

Hartl, D LengCommentNew York, N.Y.1997/06/13Science. 1997 Jun 13;276(5319):1659-60.

}, month = {Jun 13}, pages = {1659-60}, keywords = {*DNA Transposable Elements, Animals, DNA Nucleotidyltransferases/chemistry/*genetics, Drosophila/genetics, Genes, Protozoan, Genome, Protozoan, Leishmania major/*genetics, Mutagenesis, Insertional, Transfection, Transposases}, isbn = {0036-8075 (Print)0036-8075 (Linking)}, author = {Hartl, D. L.} } @article {539301, title = {Modern thoughts on an ancyent marinere: function, evolution, regulation}, journal = {Annu Rev Genet}, volume = {31}, year = {1997}, note = {

Hartl, D LLohe, A RLozovskaya, E RengGM33741/GM/NIGMS NIH HHS/Research Support, U.S. Gov{\textquoteright}t, P.H.S.Review1997/01/01 00:00Annu Rev Genet. 1997;31:337-58.

}, pages = {337-58}, abstract = {

The mariner/Tc1 superfamily of transposable elements is one of the most diverse and widespread Class II transposable elements. Within the larger assemblage, the mariner-like elements (MLEs) and the Tc1-like elements (TLEs) are distinct families differing characteristically in the composition of the "D,D(35)E" cation-binding domain. Based on levels of sequence similarity, the elements in each family can be subdivided further into several smaller subfamilies. MLEs and TLEs both have an extraordinarily wide host range. They are abundant in insect genomes and other invertebrates and are found even in some vertebrate species including, in the case of mariner, humans, in which one element on chromosome 17p has been implicated as a hotspot of recombination. In spite of the extraordinary evolutionary success of the elements, virtually nothing is known about their mode of regulation within genomes. There is abundant evidence that the elements are disseminated to naive host genomes by horizontal transmission, and there is a substantial base of evidence for inference about the subsequent population dynamics. Studies of engineered mariner elements and induced mutations in the transposase have identified two mechanisms that may be operative in mariner regulation. One mechanism is overproduction inhibition, in which excessive wild-type transposase reduces the rate of excision of a target element. A second mechanism is dominant-negative complementation, in which certain mutant transposase proteins antagonize the activity of the wild-type transposase. The latter process may help explain why the vast majority of MLEs in nature undergo "vertical inactivation" by multiple mutations and, eventually, stochastic loss. There is also evidence that mariner/Tc1 elements can be mobilized in hybrid dysgenesis; in particular, certain dysgenic crosses in Drosophila virilis result in mobilization of a TLE designated Paris as well as the mobilization of other unrelated transposable elements.

}, keywords = {*DNA Transposable Elements, Animals, Evolution, Molecular, Gene Expression Regulation, Humans}, isbn = {0066-4197 (Print)0066-4197 (Linking)}, author = {Hartl, D. L. and Lohe, A. R. and Lozovskaya, E. R.} } @article {539586, title = {Mutations in the mariner transposase: the D,D(35)E consensus sequence is nonfunctional}, journal = {Proc Natl Acad Sci U S A}, volume = {94}, number = {4}, year = {1997}, note = {

Lohe, A RDe Aguiar, DHartl, D LengGM33741/GM/NIGMS NIH HHS/Research Support, U.S. Gov{\textquoteright}t, P.H.S.1997/02/18Proc Natl Acad Sci U S A. 1997 Feb 18;94(4):1293-7.

}, month = {Feb 18}, pages = {1293-7}, abstract = {

Genetic analysis of eukaryote transposases and comparison with their prokaryote counterparts have been greatly hindered by difficulty in isolating mutations. We describe a simple eye-color screen that facilitates isolation and analysis of mutations in the mariner transposase in Drosophila melanogaster. Use of ethyl methanesulfonate and site-directed mutagenesis has identified 18 residues that are critical for in vivo excision of a target mariner element. When the mutations were examined in heterozygous mutant/nonmutant genotypes, more than half of the mutant transposase proteins were found to reduce the activity of the wild-type transposase, as assayed by the frequency of germline excision of a target element. Remarkably, transposase function is obliterated when the D,D(34)D acidic, ion-binding domain is replaced with the consensus sequence D,D(34)E found in the nematode Tc1 transposase and in many other transposases in the superfamily. A number of mutations strongly complement wild-type transposase in a dominant-negative manner, suggestive of subunit interactions in the excision reaction; these mutations are located in a small region that includes part of the D,D(34)D motif. Transposase function also is eliminated by a mutation in the inferred initiation codon and by a mutation in a putative nuclear localization signal.

}, keywords = {*Consensus Sequence, Animals, Base Sequence, Crosses, Genetic, DNA Mutational Analysis, DNA Nucleotidyltransferases/*genetics, DNA Transposable Elements/*genetics, Drosophila melanogaster/enzymology/*genetics, Genetic Complementation Test, Germ Cells/enzymology, Molecular Sequence Data, Mutagenesis, Site-Directed, Peptide Fragments/genetics, Polymerase Chain Reaction, Sequence Analysis, DNA, Sequence Deletion, Transposases}, isbn = {0027-8424 (Print)0027-8424 (Linking)}, author = {Lohe, A. R. and De Aguiar, D. and Hartl, D. L.} } @article {538606, title = {Nonrandom location of IS1 elements in the genomes of natural isolates of Escherichia coli}, journal = {Mol Biol Evol}, volume = {14}, number = {7}, year = {1997}, note = {

Boyd, E FHartl, D LengResearch Support, U.S. Gov{\textquoteright}t, P.H.S.1997/07/01Mol Biol Evol. 1997 Jul;14(7):725-32.

}, month = {Jul}, pages = {725-32}, abstract = {

We have studied the spatial distribution of IS1 elements in the genomes of natural isolates comprising the ECOR reference collection of Escherichia coli. We find evidence for nonrandomness at three levels. Many pairs of IS1 elements are in much closer proximity (\< 10 kb) than can be accounted for by chance. IS1 elements in close proximity were identified by long-range PCR amplification of the genomic sequence between them. Each amplified region was sequenced and its map location determined by database screening of DNA hybridization. Among the ECOR strains with at least two IS1 elements, 54\% had one or more pairs of elements separated by \< 10 kb. We propose that this type of clustering is a result of "local hopping," in which we assume that a significant proportion of tranposition events leads to the insertion of a daughter IS element in the vicinity of the parental element. A second level of nonrandomness is found in strains with a modest number of IS1 elements that are mapped through the use of inverse PCR to amplify flanking genomic sequences: in these strains, the insertion sites tend to be clustered over a smaller region of chromosome than would be expected by chance. A third level of nonrandomness is observed in the composite distribution of IS elements across strains: among 20 mapped IS1 elements, none were found in the region of 48-77 minutes, a significant gap. One region of the E. coli chromosome, at 98 min, had a cluster of IS1 elements in seven ECOR strains of diverse phylogenetic origin. We deduce from sequence analysis that this pattern of distribution is a result of initial insertion in the most recent common ancestor of these strains and therefore not a hot spot of insertion. Analysis using long-range PCR with primers for IS2 and IS3 also yielded pairs of elements in close proximity, suggesting that these elements may also occasionally transpose by local hopping.

}, keywords = {*DNA Transposable Elements, Chromosome Mapping, Chromosomes, Bacterial/ultrastructure, DNA, Bacterial/*genetics, Escherichia coli/*genetics/isolation \& purification, Genetic Linkage, Phylogeny}, isbn = {0737-4038 (Print)0737-4038 (Linking)}, author = {Boyd, E. F. and Hartl, D. L.} } @article {538611, title = {Recent horizontal transmission of plasmids between natural populations of Escherichia coli and Salmonella enterica}, journal = {J Bacteriol}, volume = {179}, number = {5}, year = {1997}, note = {

Boyd, E FHartl, D LengGM40322/GM/NIGMS NIH HHS/Research Support, U.S. Gov{\textquoteright}t, P.H.S.1997/03/01J Bacteriol. 1997 Mar;179(5):1622-7.

}, month = {Mar}, pages = {1622-7}, abstract = {

Seventy-one natural isolates obtained from a Salmonella reference collection were examined for the presence of plasmids closely related to the Escherichia coli F plasmid. The collection consists of several serovars of the S. enterica Typhimurium complex, subspecies I, to which 99\% of pathogenic salmonellae belong. Molecular genetic techniques of DNA hybridization, along with PCR and DNA sequencing, were used to examine the occurrence, distribution, and genetic diversity of F-like plasmids among Salmonella strains. The F plasmid genes examined were finO, traD, traY, and repA, which map at dispersed positions on the F plasmid of E. coli. Comparative sequence analysis of each of the four genes in Salmonella plasmids showed them to be homologous (in some cases, virtually identical) to those found in F plasmids of E. coli natural isolates. Furthermore, the frequency of F-like plasmids in Salmonella strains was approximately the same as that observed in the E. coli Reference Collection. However, in Salmonella, the distribution was confined predominately to the serovars Typhimurium and Muenchen. The unexpected finding of a shared pool of F-like plasmids between S. enterica and E. coli demonstrates the significant role of conjugation in the histories of these important bacterial species.

}, keywords = {*Conjugation, Genetic, *DNA Helicases, *Escherichia coli Proteins, *F Factor, *Membrane Proteins, *Repressor Proteins, *RNA-Binding Proteins, *Trans-Activators, Amino Acid Sequence, Bacterial Proteins/chemistry/genetics, DNA-Binding Proteins/chemistry/genetics, Escherichia coli/*genetics, Molecular Sequence Data, Phylogeny, Polymerase Chain Reaction, Polymorphism, Genetic, Proteins/chemistry/genetics, Salmonella typhimurium/*genetics, Salmonella/*genetics}, isbn = {0021-9193 (Print)0021-9193 (Linking)}, author = {Boyd, E. F. and Hartl, D. L.} } @article {539306, title = {Regulation of the transposable element mariner}, journal = {Genetica}, volume = {100}, number = {1-3}, year = {1997}, note = {

Hartl, D LLohe, A RLozovskaya, E RengGM33741/GM/NIGMS NIH HHS/Research Support, U.S. Gov{\textquoteright}t, P.H.S.ReviewNETHERLANDS1997/01/01 00:00Genetica. 1997;100(1-3):177-84.

}, pages = {177-84}, abstract = {

The mariner/Tcl superfamily of transposable elements is widely distributed in animal genomes and is especially prevalent in insects. Their wide distribution results from their ability to be disseminated among hosts by horizontal transmission and also by their ability to persist in genomes through multiple speciation events. Although a great deal is known about the molecular mechanisms of transposition and excision, very little is known about the mechanisms by which transposition is controlled within genomes. The issue of mariner/Tcl regulation is critical in view of the great interest in these elements as vectors for germline transformation of insect pests and vectors of human disease. Several potentially important regulatory mechanisms have been identified in studies of genetically engineered mariner elements. One mechanism is overproduction inhibition, in which excessive wild-type transposase reduces the rate of excision of a target element. A second mechanism is mediated by certain mutant transposase proteins, which antagonize the activity of the wild-type transposase. The latter process may help explain why the vast majority of MLEs in nature undergo {\textquoteright}vertical inactivation{\textquoteright} by multiple mutations and, eventually, stochastic loss. Another potential mechanism of regulation may result from transposase titration by defective elements that retain their DNA binding sites and ability to transpose. There is also evidence that some mariner/Tcl elements can be mobilized in a type of hybrid dysgenesis.

}, keywords = {Animals, DNA Transposable Elements/*genetics, Gene Expression Regulation/*physiology, Genes, Dominant, Genetic Complementation Test, genome, Humans, Mutation, Transformation, Genetic, Transposases/genetics}, isbn = {0016-6707 (Print)0016-6707 (Linking)}, author = {Hartl, D. L. and Lohe, A. R. and Lozovskaya, E. R.} } @article {539856, title = {Trash DNA is what gets thrown away: high rate of DNA loss in Drosophila}, journal = {Gene}, volume = {205}, number = {1-2}, year = {1997}, note = {

Petrov, D AHartl, D LengGM33741/GM/NIGMS NIH HHS/HG01250/HG/NHGRI NIH HHS/Research Support, U.S. Gov{\textquoteright}t, P.H.S.NETHERLANDS1998/02/14Gene. 1997 Dec 31;205(1-2):279-89.

}, month = {Dec 31}, pages = {279-89}, abstract = {

We have recently described a novel method of estimating neutral rates and patterns of spontaneous mutation (Petrov et al., 1996). This method takes advantage of the propensity of non-LTR retrotransposable elements to create non-functional, {\textquoteright}dead-on-arrival{\textquoteright} copies as a product of transposition. Maximum parsimony analysis is used to separate the evolution of actively transposing lineages of a non-LTR element from the fate of individual inactive insertions, and thereby allows one to assess directly the relative rates of different types of mutation, including point substitutions, deletions and insertions. Because non-LTR elements enjoy wide phylogenetic distribution, this method can be used in taxa that do not harbor a significant number of bona fide pseudogenes, as is the case in Drosophila (Jeffs and Ashburner, 1991; Weiner et al., 1986). We used this method with Helena, a non-LTR retrotransposable element present in the Drosophila virilis species group. A striking finding was the virtual absence of insertions and remarkably high incidence of large deletions, which combine to produce a high overall rate of DNA loss. On average, the rate of DNA loss in D. virilis is approximately 75 times faster than that estimated for mammalian pseudogenes (Petrov et al., 1996). The high rate of DNA loss should lead to rapid elimination of non-essential DNA and thus may explain the seemingly paradoxical dearth of pseudogenes in Drosophila. Varying rates of DNA loss may also contribute to differences in genome size (Graur et al., 1989; Petrov et al., 1996), thus explaining the celebrated {\textquoteright}C-value{\textquoteright} paradox (John and Miklos, 1988). In this paper we outline the theoretical basis of our method, examine the data from this perspective, and discuss potential problems that may bias our estimates.

}, keywords = {Animals, DNA/*genetics, Drosophila/*genetics, Phylogeny, Pseudogenes, Retroelements, Selection, Genetic}, isbn = {0378-1119 (Print)0378-1119 (Linking)}, author = {Petrov, D. A. and Hartl, D. L.} } @article {539326, title = {What restricts the activity of mariner-like transposable elements}, journal = {Trends Genet}, volume = {13}, number = {5}, year = {1997}, note = {

Hartl, D LLozovskaya, E RNurminsky, D ILohe, A RengGM33741/GM/NIGMS NIH HHS/Research Support, U.S. Gov{\textquoteright}t, P.H.S.ENGLAND1997/05/01Trends Genet. 1997 May;13(5):197-201.

}, month = {May}, pages = {197-201}, abstract = {

A number of mechanisms have recently been described that might be important in restricting the level of activity of mariner-like transposable elements (MLEs) in natural populations. These mechanisms include overproduction inhibition, in which increasing the dose of transposase decreases net activity. Another mechanism is mediated by certain missense mutations, in which a mutant transposase protein impairs the activity of the wild-type transposase in heterozygous mutant/nonmutant genotypes. A further mechanism is the potential for transposase titration by defective elements that retain transposase binding activity. The issue of regulation is not only of theoretical importance in understanding the molecular and evolutionary genetics of MLEs, but also of practical significance in learning how best to use MLEs in the germline transformation of insect pests and disease vectors.

}, keywords = {Animals, DNA Nucleotidyltransferases/*physiology, DNA Transposable Elements/*physiology, Drosophila/*genetics, Humans, Transposases}, isbn = {0168-9525 (Print)0168-9525 (Linking)}, author = {Hartl, D. L. and Lozovskaya, E. R. and Nurminsky, D. I. and Lohe, A. R.} } @article {539601, title = {Autoregulation of mariner transposase activity by overproduction and dominant-negative complementation}, journal = {Mol Biol Evol}, volume = {13}, number = {4}, year = {1996}, note = {

Lohe, A RHartl, D LengGM33741/GM/NIGMS NIH HHS/Research Support, U.S. Gov{\textquoteright}t, P.H.S.1996/04/01Mol Biol Evol. 1996 Apr;13(4):549-55.

}, month = {Apr}, pages = {549-55}, abstract = {

Genetic studies of the mariner transposable element Mos1 have revealed two novel types of regulatory mechanisms. In one mechanism, overproduction of the wild-type transposase reduces the overall level of transposase activity as assayed by the excision of a nonautonomous mariner target element. This mechanism is termed overproduction inhibition (OPI). Another mechanism is observed in a class of hypomorphic missense mutations in the transposase. In the presence of wild-type Mos1 transposase, these mutations exhibit dominant-negative complementation (DNC) that antagonizes the activity of the wild-type transposase. We propose that these regulatory mechanisms act at the level of the transposase protein subunits by promoting the assembly of oligomeric forms, or of mixed-subunit oligomers, that have reduced activity. We suggest that these regulatory mechanisms may apply generally to mariner-like elements (MLEs). Overproduction inhibition may help explain why the MLE copy number reaches very different levels in different species. Dominant-negative complementation may help explain why most naturally occurring copies of MLEs have been mutationally inactivated.

}, keywords = {*Gene Expression Regulation, Animals, DNA Nucleotidyltransferases/*genetics/metabolism, Drosophila/genetics, Gene Dosage, Genes, Dominant, Mutation, Transposases}, isbn = {0737-4038 (Print)0737-4038 (Linking)}, author = {Lohe, A. R. and Hartl, D. L.} } @article {539371, title = {Compensatory nearly neutral mutations: selection without adaptation}, journal = {J Theor Biol}, volume = {182}, number = {3}, year = {1996}, note = {

Hartl, D LTaubes, C HengResearch Support, U.S. Gov{\textquoteright}t, Non-P.H.S.Research Support, U.S. Gov{\textquoteright}t, P.H.S.ENGLAND1996/10/07J Theor Biol. 1996 Oct 7;182(3):303-9.

}, month = {Oct 7}, pages = {303-9}, abstract = {

One implication of Kacser{\textquoteright}s analysis of complex metabolic systems is that mutations with small effects exist as a consequence of the typically small flux control coefficient relating enzyme activity to the rate of a metabolic process. Although a slightly detrimental mutation is somewhat less likely to become fixed by chance than a slightly favorable mutation, mutations that are slightly detrimental might be expected to be more numerous than favorable mutations owing to the previous incorporation of favorable mutations by a long history of natural selection. The result is that, as Ohta has pointed out, a significant fraction of mutations that are fixed in evolution are slightly detrimental. In the long run, the fixation of detrimental mutations in a gene increases the opportunity for the occurrence of a compensatory favorable mutation, either in the same gene or in an interacting gene. On a suitably long timescale, therefore, every gene incorporates favorable mutations that compensate for detrimental mutations previously fixed. This form of evolution is driven primarily by natural selection, but it results in no change or permanent improvement in enzymatic function.

}, keywords = {*Mutation, *Selection, Genetic, Adaptation, Physiological/genetics, Animals, Enzymes/*genetics/metabolism, Models, Genetic}, isbn = {0022-5193 (Print)0022-5193 (Linking)}, author = {Hartl, D. L. and Taubes, C. H.} } @article {539176, title = {Est! Est!! Est!!!}, journal = {Bioessays}, volume = {18}, number = {12}, year = {1996}, note = {

Hartl, D LengReviewENGLAND1996/12/01Bioessays. 1996 Dec;18(12):1021-3.

}, month = {Dec}, pages = {1021-3}, abstract = {

A recently published study has identified a set of candidate genes for human diseases based on findings from Drosophila. Each human expressed sequence tag (EST) in a large database was compared with all known Drosophila genes. After eliminating matches between genes of already known function, the remaining sequences were mapped in the human genome. In each region, the phenotypes of all known human diseases were compared with the phenotypes of known Drosophila mutations in order to identify candidate genes for the human diseases. Are the correspondences real or coincidental?

}, keywords = {*Genetic Techniques, *Genome, Human, Animals, Chromosome Mapping, Databases, Factual, Drosophila/genetics, Genetic Diseases, Inborn/*genetics, Humans, In Situ Hybridization, Fluorescence, Mutation, Phenotype}, isbn = {0265-9247 (Print)0265-9247 (Linking)}, author = {Hartl, D. L.} } @article {539636, title = {Germline transformation of Drosophila virilis mediated by the transposable element hobo}, journal = {Genetics}, volume = {142}, number = {1}, year = {1996}, note = {

Lozovskaya, E RNurminsky, D IHartl, D LSullivan, D TengGM-33741/GM/NIGMS NIH HHS/Research Support, U.S. Gov{\textquoteright}t, P.H.S.1996/01/01Genetics. 1996 Jan;142(1):173-7.

}, month = {Jan}, pages = {173-7}, abstract = {

A laboratory strain of Drosophila virilis was genetically transformed with a hobo vector carrying the miniwhite cassette using a helper plasmid with an hsp70-driven hobo transposase-coding sequence. The rate of transformation was 0.5\% per fertile GO animal. Three transgenic insertions were cloned and characterized and found to be authentic hobo insertions. These results, together with the known widespread distribution of hobo in diverse insect species, suggest that hobo and related transposable elements may be of considerable utility in the germline transformation of insects other than D. melanogaster.

}, keywords = {*DNA Transposable Elements, *Transformation, Genetic, Animals, Base Sequence, Cloning, Molecular, DNA Nucleotidyltransferases/genetics, DNA Primers/genetics, Drosophila/*genetics, Female, Genetic Vectors, HSP70 Heat-Shock Proteins/genetics, In Situ Hybridization, Male, Molecular Sequence Data, Plasmids/genetics, Repetitive Sequences, Nucleic Acid, Transposases}, isbn = {0016-6731 (Print)0016-6731 (Linking)}, author = {Lozovskaya, E. R. and Nurminsky, D. I. and Hartl, D. L. and Sullivan, D. T.} } @article {539596, title = {Germline transformation of Drosophila virilis with the transposable element mariner}, journal = {Genetics}, volume = {143}, number = {1}, year = {1996}, note = {

Lohe, A RHartl, D LengGM-33741/GM/NIGMS NIH HHS/Research Support, U.S. Gov{\textquoteright}t, P.H.S.1996/05/01Genetics. 1996 May;143(1):365-74.

}, month = {May}, pages = {365-74}, abstract = {

An important goal in molecular genetics has been to identify a transposable element that might serve as an efficient transformation vector in diverse species of insects. The transposable element mariner occurs naturally in a wide variety of insects. Although virtually all mariner elements are nonfunctional, the Mos1 element isolated from Drosophila mauritiana is functional. Mos1 was injected into the pole-cell region of embryos of D. virilis, which last shared a common ancestor with D. mauritiana 40 million years ago. Mos1 PCR fragments were detected in several pools of DNA from progeny of injected animals, and backcross lines were established. Because G0 lines were pooled, possibly only one transformation event was actually obtained, yielding a minimum frequency of 4\%. Mos1 segregated in a Mendelian fashion, demonstrating chromosomal integration. The copy number increased by spontaneous mobilization. In situ hybridization confirmed multiple polymorphic locations of Mos1. Integration results in a characteristic 2-bp TA duplication. One Mos1 element integrated into a tandem array of 370-bp repeats. Some copies may have integrated into heterochromatin, as evidenced by their ability to support PCR amplification despite absence of a signal in Southern and in situ hybridization.

}, keywords = {*DNA Transposable Elements, *Transformation, Genetic, Animals, Base Sequence, Chromosome Deletion, Chromosome Mapping, DNA Primers, Drosophila/*genetics, Embryo, Nonmammalian, genome, In Situ Hybridization, Molecular Sequence Data, Polymerase Chain Reaction, Polymorphism, Genetic, Repetitive Sequences, Nucleic Acid}, isbn = {0016-6731 (Print)0016-6731 (Linking)}, author = {Lohe, A. R. and Hartl, D. L.} } @article {539876, title = {High intrinsic rate of DNA loss in Drosophila}, journal = {Nature}, volume = {384}, number = {6607}, year = {1996}, note = {

Petrov, D ALozovskaya, E RHartl, D LengResearch Support, U.S. Gov{\textquoteright}t, P.H.S.ENGLAND1996/11/28Nature. 1996 Nov 28;384(6607):346-9.

}, month = {Nov 28}, pages = {346-9}, abstract = {

Pseudogenes are common in mammals but virtually absent in Drosophila. All putative Drosophila pseudogenes show patterns of molecular evolution that are inconsistent with the lack of functional constraints. The absence of bona fide pseudogenes is not only puzzling, it also hampers attempts to estimate rates and patterns of neutral DNA change. The estimation problem is especially acute in the case of deletions and insertions, which are likely to have large effects when they occur in functional genes and are therefore subject to strong purifying selection. We propose a solution to this problem by taking advantage of the propensity of retrotransposable elements without long terminal repeats (non-LTR) to create non-functional, {\textquoteright}dead-on-arrival{\textquoteright} copies of themselves as a common by-product of their transpositional cycle. Phylogenetic analysis of a non-LTR element, Helena, demonstrates that copies lose DNA at an unusually high rate, suggesting that lack of pseudogenes in Drosophila is the product of rampant deletion of DNA in unconstrained regions. This finding has important implications for the study of genome evolution in general and the {\textquoteright}C-value paradox{\textquoteright} in particular.

}, keywords = {*Dna, *Evolution, Molecular, *Retroelements, *Sequence Deletion, Animals, Cloning, Molecular, Drosophila/classification/*genetics, Molecular Sequence Data, Phylogeny, Pseudogenes, RNA-Directed DNA Polymerase/genetics}, isbn = {0028-0836 (Print)0028-0836 (Linking)}, author = {Petrov, D. A. and Lozovskaya, E. R. and Hartl, D. L.} } @article {539356, title = {Inverse polymerase chain reaction}, journal = {Methods Mol Biol}, volume = {58}, year = {1996}, note = {

Hartl, D LOchman, HengGM40322/GM/NIGMS NIH HHS/GM40995/GM/NIGMS NIH HHS/HG00357/HG/NHGRI NIH HHS/Research Support, U.S. Gov{\textquoteright}t, P.H.S.Clifton, N.J.1996/01/01Methods Mol Biol. 1996;58:293-301.

}, pages = {293-301}, keywords = {DNA Ligases/genetics, DNA Primers/genetics, DNA Restriction Enzymes, Polymerase Chain Reaction/*methods}, isbn = {1064-3745 (Print)1064-3745 (Linking)}, author = {Hartl, D. L. and Ochman, H.} } @article {539786, title = {Molecular phylogeny and genome evolution in the Drosophila virilis species group: duplications of the alcohol dehydrogenase gene}, journal = {Mol Biol Evol}, volume = {13}, number = {1}, year = {1996}, note = {

Nurminsky, D IMoriyama, E NLozovskaya, E RHartl, D LengGM33741/GM/NIGMS NIH HHS/Research Support, U.S. Gov{\textquoteright}t, P.H.S.1996/01/01Mol Biol Evol. 1996 Jan;13(1):132-49.

}, month = {Jan}, pages = {132-49}, abstract = {

Drosophila virilis is a prominent reference species for comparison with Drosophila melanogaster in regard to patterns and mechanisms of molecular and genomic evolution. Sequences were determined for 11 Adh genes from 8 species of the D. virilis species group, including species from both the virilis phylad and the montana subphylad. The genome of D. virilis contains a 6-kb duplication that includes the entire Adh coding region. The pattern of sequence identity within the duplication strongly suggests a recent gene-conversion event bordered by 36-bp indels. As in other Drosophila, the amino-acid coding region of Adh is encoded by three exons interrupted by two short introns. The promoter region includes 16 blocks of sequence that are well conserved in D. virilis, Drosophila hydei, and D. melanogaster. The developmental profile of Adh transcription suggests a distal/proximal promoter switch analogous to that in D. melanogaster. Duplicate Adh genes were also found in Drosophila montana and Drosophila lacicola, which apparently originated independently of that in D. virilis. The Adh genes in all species of the D. virilis group have among the lowest codon bias of any Adh genes so far reported in the genus Drosophila. Taking the low codon bias into account, we estimate the time of divergence between the virilis and montana clades as 9.0 +/- 0.7 Mya and the approximate time of divergence of D. virilis from other members of the virilis phylad as 2.6 +/- 0.4 Mya. The region of the D. virilis genome containing Adh, as well as the chromosome as a whole, gives evidence of extensive rearrangements relative to the genome of D. melanogaster.

}, keywords = {*Evolution, Molecular, Alcohol Dehydrogenase/*genetics, Amino Acid Sequence, Animals, Base Sequence, Drosophila/enzymology/*genetics, genome, Molecular Sequence Data, Phylogeny, Sequence Alignment}, isbn = {0737-4038 (Print)0737-4038 (Linking)}, author = {Nurminsky, D. I. and Moriyama, E. N. and Lozovskaya, E. R. and Hartl, D. L.} } @article {538536, title = {Molecular phylogeny of Azteca ants (Hymenoptera:Formicidae) and the colonization of Cecropia trees}, journal = {Mol Phylogenet Evol}, volume = {5}, number = {2}, year = {1996}, note = {

Ayala, F JWetterer, J KLongino, J THartl, D LengComparative Study1996/04/01Mol Phylogenet Evol. 1996 Apr;5(2):423-8.

}, month = {Apr}, pages = {423-8}, abstract = {

Despite the prominence of the Azteca-Cecropia interaction as the focus of extensive ecological investigation, a reliable phylogeny of the Azteca ants has been lacking, primarily because many of the morphological and behavioral characters are phylogenetically uninformative or conflicting. A phylogenetic analysis of a select set of Azteca ants, including six Cecropia inhabitants and two non-Cecropia inhabitants, plus an outgroup taxon, is presented on the basis of mitochondrial DNA sequences. The evolutionary relationships deduced from the molecular data are analyzed with reference to ecological and morphological studies, specifically addressing the phylogenetic relationship of structurally an behaviorally ambiguous taxa, species complex groupings, and the colonization of Cecropia trees. According to the molecular phylogeny, the Cecropia-inhabiting Azteca do not form a monophyletic clade, indicating multiple independent colonization or abandonment of Cecropia trees by the Azteca.

}, keywords = {*Phylogeny, *Trees, Animals, Ants/classification/*genetics, Base Sequence, Confidence Intervals, DNA Primers, DNA, Mitochondrial/*genetics, Electron Transport Complex IV/genetics, Molecular Sequence Data, Polymerase Chain Reaction, RNA, Transfer, Leu/genetics, Sequence Homology, Nucleic Acid, Social Behavior}, isbn = {1055-7903 (Print)1055-7903 (Linking)}, author = {Ayala, F. J. and Wetterer, J. K. and Longino, J. T. and Hartl, D. L.} } @article {538636, title = {Mosaic structure of plasmids from natural populations of Escherichia coli}, journal = {Genetics}, volume = {143}, number = {3}, year = {1996}, note = {

Boyd, E FHill, C WRich, S MHartl, D LengGM-16329/GM/NIGMS NIH HHS/GM-40322/GM/NIGMS NIH HHS/Research Support, U.S. Gov{\textquoteright}t, P.H.S.1996/07/01Genetics. 1996 Jul;143(3):1091-100.

}, month = {Jul}, pages = {1091-100}, abstract = {

The distribution of plasmids related to the fertility factor F was examined in the ECOR reference collection of Escherichia coli. Probes specific for four F-related genes were isolated and used to survey the collection by DNA hybridization. To estimate the genetic diversity of genes in F-like plasmids, DNA sequences were obtained for four plasmid genes. The phylogenetic relationships among the plasmids in the ECOR strains is very different from that of the strains themselves. This finding supports the view that plasmid transfer has been frequent within and between the major groups of ECOR. Furthermore, the sequences indicate that recombination between genes in plasmids takes place at a considerably higher frequency than that observed for chromosomal genes. The plasmid genes, and by inference the plasmids themselves, are mosaic in structure with different regions acquired from different sources. Comparison of gene sequences from a variety of naturally occurring plasmids suggested a plausible donor of some of the recombinant regions as well as implicating a chi site in the mechanism of genetic exchange. The relatively high rate of recombination in F-plasmid genes suggests that conjugational gene transfer may play a greater role in bacterial population structure than previously appreciated.

}, keywords = {*DNA Helicases, *DNA-Binding Proteins, *Escherichia coli Proteins, *Membrane Proteins, *Repressor Proteins, *RNA-Binding Proteins, *Trans-Activators, Bacterial Proteins/classification/*genetics, Base Sequence, DNA, Bacterial, Escherichia coli/classification/*genetics, Evolution, Molecular, Molecular Sequence Data, Mosaicism, Nucleic Acid Hybridization, Phylogeny, Plasmids/genetics, Polymorphism, Genetic, Proteins/classification/*genetics, Recombination, Genetic}, isbn = {0016-6731 (Print)0016-6731 (Linking)}, author = {Boyd, E. F. and Hill, C. W. and Rich, S. M. and Hartl, D. L.} } @article {539181, title = {The most unkindest cut of all}, journal = {Nat Genet}, volume = {12}, number = {3}, year = {1996}, note = {

Hartl, D LengCommentNews1996/03/01Nat Genet. 1996 Mar;12(3):227-9.

}, month = {Mar}, pages = {227-9}, keywords = {*Chromosomes, Human, Pair 17, *Genes, Insect, *Recombination, Genetic, Animals, Charcot-Marie-Tooth Disease/genetics, DNA Transposable Elements, Drosophila/genetics, Humans, Myelin Proteins/genetics, Peripheral Nervous System Diseases/genetics}, isbn = {1061-4036 (Print)1061-4036 (Linking)}, author = {Hartl, D. L.} } @article {538516, title = {A new Borrelia infecting Lone Star ticks}, journal = {Lancet}, volume = {347}, number = {8993}, year = {1996}, note = {

Armstrong, P MRich, S MSmith, R DHartl, D LSpielman, ATelford, S R 3rdengAI 19693/AI/NIAID NIH HHS/AI 37993/AI/NIAID NIH HHS/LetterResearch Support, Non-U.S. Gov{\textquoteright}tResearch Support, U.S. Gov{\textquoteright}t, P.H.S.ENGLAND1996/01/06Lancet. 1996 Jan 6;347(8993):67-8.

}, month = {Jan 6}, pages = {67-8}, keywords = {Animals, Base Sequence, Borrelia Infections/microbiology, Borrelia/classification/*isolation \& purification, Deer, Disease Vectors, DNA Primers, Maryland, Molecular Sequence Data, Ticks/*microbiology}, isbn = {0140-6736 (Print)0140-6736 (Linking)}, author = {Armstrong, P. M. and Rich, S. M. and Smith, R. D. and Hartl, D. L. and Spielman, A. and Telford, S. R., 3rd} } @article {539926, title = {Reconstructing the ancient mariners of humans}, journal = {Nat Genet}, volume = {12}, number = {4}, year = {1996}, note = {

Robertson, H MZumpano, K LLohe, A RHartl, D LengLetter1996/04/01Nat Genet. 1996 Apr;12(4):360-1.

}, month = {Apr}, pages = {360-1}, keywords = {*DNA Transposable Elements, *Genome, Human, Amino Acid Sequence, Animals, Biological Evolution, Consensus Sequence, DNA Nucleotidyltransferases/genetics, Humans, Molecular Sequence Data, Sequence Homology, Amino Acid, Transposases}, isbn = {1061-4036 (Print)1061-4036 (Linking)}, author = {Robertson, H. M. and Zumpano, K. L. and Lohe, A. R. and Hartl, D. L.} } @article {539591, title = {Reduced germline mobility of a mariner vector containing exogenous DNA: effect of size or site?}, journal = {Genetics}, volume = {143}, number = {3}, year = {1996}, note = {

Lohe, A RHartl, D LengGM-33741/GM/NIGMS NIH HHS/Research Support, U.S. Gov{\textquoteright}t, P.H.S.1996/07/01Genetics. 1996 Jul;143(3):1299-306.

}, month = {Jul}, pages = {1299-306}, abstract = {

Germline mobilization of the transposable element mariner is severely inhibited by the insertion of a 4.5- to 11.9-kb fragment of exogenous DNA into a unique SacI site approximately in the middle of the 1286-bp element. In the presence of transposase driven by the germline-specific hsp26-sgs3 promoter, mobilization of the MlwB construct (containing a 11.9-kb insertion) is detected at low frequency. Analysis of a mobilized MlwB element indicated that mobilization is mediated by the mariner transposase. However, transposed MlwB elements are also defective in germline mobilization. Rare, transposase-induced germline excision events were also recovered for such vectors. The estimated rate of excision is \< 0.1\% per chromosome per generation. Excision appears to be accompanied by gap repair if a suitable template is available. The data imply that the reduced mobility of mariner vectors with exogenous DNA in the SacI site results from disruption of sequences necessary for efficient mobilization. The relative stability may be a valuable property in the uses of mariner-like elements in genetic engineering of insects of economic importance.

}, keywords = {*DNA Transposable Elements, *Genetic Vectors, Animals, Base Sequence, DNA Nucleotidyltransferases, Drosophila/*genetics, Female, Male, Molecular Sequence Data, Transformation, Genetic, Transposases}, isbn = {0016-6731 (Print)0016-6731 (Linking)}, author = {Lohe, A. R. and Hartl, D. L.} } @article {539781, title = {Sequence scanning: A method for rapid sequence acquisition from large-fragment DNA clones}, journal = {Proc Natl Acad Sci U S A}, volume = {93}, number = {4}, year = {1996}, note = {

Nurminsky, D IHartl, D LengHG01250/HG/NHGRI NIH HHS/Research Support, U.S. Gov{\textquoteright}t, P.H.S.1996/02/20Proc Natl Acad Sci U S A. 1996 Feb 20;93(4):1694-8.

}, month = {Feb 20}, pages = {1694-8}, abstract = {

A strategy of "sequence scanning" is proposed for rapid acquisition of sequence from clones such as bacteriophage P1 clones, cosmids, or yeast artificial chromosomes. The approach makes use of a special vector, called LambdaScan, that reliably yields subclones with inserts in the size range 8-12 kb. A number of subclones, typically 96 or 192, are chosen at random, and the ends of the inserts are sequenced using vector-specific primers. Then long-range spectrum PCR is used to order and orient the clones. This combination of shotgun and directed sequencing results in a high-resolution physical map suitable for the identification of coding regions or for comparison of sequence organization among genomes. Computer simulations indicate that, for a target clone of 100 kb, the scanning of 192 subclones with sequencing reads as short as 350 bp results in an approximate ratio of 1:2:1 of regions of double-stranded sequence, single-stranded sequence, and gaps. Longer sequencing reads tip the ratio strongly toward increased double-stranded sequence.

}, keywords = {*Genetic Vectors, Animals, Cloning, Molecular/methods, DNA, Recombinant/*chemistry, Drosophila/genetics, Molecular Sequence Data, Polymerase Chain Reaction, Sequence Analysis, DNA/*methods, Templates, Genetic}, isbn = {0027-8424 (Print)0027-8424 (Linking)}, author = {Nurminsky, D. I. and Hartl, D. L.} } @article {539621, title = {Subunit interactions in the mariner transposase}, journal = {Genetics}, volume = {144}, number = {3}, year = {1996}, note = {

Lohe, A RSullivan, D THartl, D LengGM-33741/GM/NIGMS NIH HHS/Research Support, U.S. Gov{\textquoteright}t, P.H.S.1996/11/01Genetics. 1996 Nov;144(3):1087-95.

}, month = {Nov}, pages = {1087-95}, abstract = {

We have studied the Mos1 transposase encoded by the transposable element mariner. This-transposase is a member of the "D,D(35)E" superfamily of proteins exhibiting the motif D,D(34)D. It is not known whether this transposase, or other eukaryote transposases manifesting the D,D(35)E domain, functions in a multimeric form. Evidence for oligomerization was found in the negative complementation of Mos1 by an EMS-induced transposase mutation in the catalytic domain. The transposase produced by this mutation has a glycine-to-arginine replacement at position 292. The G292R mutation strongly interferes with the ability of wild-type transposase to catalyze excision of a target element. Negative complementation was also observed for two other EMS mutations, although the effect was weaker than observed with G292R. Results from the yeast two-hybrid system also imply that Mos1 subunits interact, suggesting the possibility of subunit oligomerization in the transposition reaction. Overproduction of Mos1 subunits through an hsp70 promoter also inhibits excision of the target element, possibly through autoregulatory feedback on transcription or through formation of inactive or less active oligomers. The effects of both negative complementation and overproduction may contribute to the regulation of mariner transposition.

}, keywords = {*DNA Nucleotidyltransferases, Alleles, Animals, Drosophila melanogaster/*genetics, Female, Genetic Complementation Test, Germ Cells, HSP70 Heat-Shock Proteins/genetics, Male, Mutagenesis, Promoter Regions, Genetic, Transposases}, isbn = {0016-6731 (Print)0016-6731 (Linking)}, author = {Lohe, A. R. and Sullivan, D. T. and Hartl, D. L.} } @article {540016, title = {Transgene Coplacement and high efficiency site-specific recombination with the Cre/loxP system in Drosophila}, journal = {Genetics}, volume = {144}, number = {2}, year = {1996}, note = {

Siegal, M LHartl, D LengGM-33741/GM/NIGMS NIH HHS/HG-01250/HG/NHGRI NIH HHS/Research Support, Non-U.S. Gov{\textquoteright}tResearch Support, U.S. Gov{\textquoteright}t, P.H.S.1996/10/01Genetics. 1996 Oct;144(2):715-26.

}, month = {Oct}, pages = {715-26}, abstract = {

Studies of gene function and regulation in transgenic Drosophila are often compromised by the possibility of genomic position effects on gene expression. We have developed a method called transgene coplacement, in which any two sequences can be positioned at exactly the same site and orientation in the genome. Transgene coplacement makes use of the bacteriophage P1 system of Cre/loxP site-specific recombination, which we have introduced into Drosophila. In the presence of a cre transgene driven by a dual hsp70-Mos1 promoter, a white reporter gene flanked by loxP sites is excised with virtually 100\% efficiency both in somatic cells and in germ cells. A strong maternal effect, resulting from Cre recombinase present in the oocyte, is observed as white or mosaic eye color in F1 progeny. Excision in germ cells of the F1 yields a strong grand-maternal effect, observed as a highly skewed ratio of eye-color phenotypes in the F2 generation. The excision reactions of Cre/loxP and the related FLP/FRT system are used to create Drosophila lines in which transgenes are at exactly allelic sites in homologous chromosomes.

}, keywords = {*ATP-Binding Cassette Transporters, *Drosophila Proteins, *Eye Proteins, *Genes, Reporter, *Recombination, Genetic, *Viral Proteins, Animals, Animals, Genetically Modified, Base Sequence, DNA, Female, Gene Expression, Germ Cells, Insect Hormones/*genetics, Integrases/genetics/*metabolism, Male, Molecular Sequence Data, Transgenes}, isbn = {0016-6731 (Print)0016-6731 (Linking)}, author = {Siegal, M. L. and Hartl, D. L.} } @article {539916, title = {Distribution of the Ixodes ricinus-like ticks of eastern North America}, journal = {Proc Natl Acad Sci U S A}, volume = {92}, number = {14}, year = {1995}, note = {

Rich, S MCaporale, D ATelford, S R 3rdKocher, T DHartl, D LSpielman, AengAI 19693/AI/NIAID NIH HHS/Comparative StudyResearch Support, U.S. Gov{\textquoteright}t, Non-P.H.S.Research Support, U.S. Gov{\textquoteright}t, P.H.S.1995/07/03Proc Natl Acad Sci U S A. 1995 Jul 3;92(14):6284-8.

}, month = {Jul 3}, pages = {6284-8}, abstract = {

We analyzed the geographic distribution of the Ixodes ricinus-like ticks in eastern North America by comparing the mitochondrial 16S rDNA sequences of specimens sampled directly from the field during the 1990s. Two distinct lineages are evident. The southern clade includes ticks from the southeastern and middle-eastern regions of the United States. The range of the northern clade, which appears to have been restricted to the northeastern region until the mid-1900s, now extends throughout the northeastern and middle-eastern regions. These phyletic units correspond to northern and southern taxa that have previously been assigned specific status as Ixodes dammini and Ixodes scapularis, respectively. The expanding range of I. dammini appears to drive the present outbreaks of zoonotic disease in eastern North America that include Lyme disease and human babesiosis.

}, keywords = {*Phylogeny, Animals, Base Sequence, demography, DNA Primers, DNA, Mitochondrial/genetics, DNA, Ribosomal/*genetics, Geography, Mitochondria/metabolism, Molecular Sequence Data, Polymerase Chain Reaction, Population, RNA, Ribosomal, 16S/*genetics, Ticks/classification/*genetics, United States}, isbn = {0027-8424 (Print)0027-8424 (Linking)}, author = {Rich, S. M. and Caporale, D. A. and Telford, S. R., 3rd and Kocher, TD and Hartl, D. L. and Spielman, A.} } @article {539886, title = {Diverse transposable elements are mobilized in hybrid dysgenesis in Drosophila virilis}, journal = {Proc Natl Acad Sci U S A}, volume = {92}, number = {17}, year = {1995}, note = {

Petrov, D ASchutzman, J LHartl, D LLozovskaya, E RengGM33741/GM/NIGMS NIH HHS/Comparative StudyResearch Support, U.S. Gov{\textquoteright}t, P.H.S.1995/08/15Proc Natl Acad Sci U S A. 1995 Aug 15;92(17):8050-4.

}, month = {Aug 15}, pages = {8050-4}, abstract = {

We describe a system of hybrid dysgenesis in Drosophila virilis in which at least four unrelated transposable elements are all mobilized following a dysgenic cross. The data are largely consistent with the superposition of at least three different systems of hybrid dysgenesis, each repressing a different transposable element, which break down following the hybrid cross, possibly because they share a common pathway in the host. The data are also consistent with a mechanism in which mobilization of a single element triggers that of others, perhaps through chromosome breakage. The mobilization of multiple, unrelated elements in hybrid dysgenesis is reminiscent of McClintock{\textquoteright}s evidence [McClintock, B. (1955) Brookhaven Symp. Biol. 8, 58-74] for simultaneous mobilization of different transposable elements in maize.

}, keywords = {*DNA Transposable Elements, *Gonadal Dysgenesis, *Mutation, Amino Acid Sequence, Animals, Chromosome Mapping, Cloning, Molecular, Crosses, Genetic, DNA/chemistry/genetics, Drosophila/*genetics, Female, Genomic Library, Male, Molecular Sequence Data, Open Reading Frames, Repetitive Sequences, Nucleic Acid, Retroelements, X Chromosome, Zea mays/genetics}, isbn = {0027-8424 (Print)0027-8424 (Linking)}, author = {Petrov, D. A. and Schutzman, J. L. and Hartl, D. L. and Lozovskaya, E. R.} } @article {539286, title = {Genome evolution comes of age}, journal = {Curr Opin Genet Dev}, volume = {5}, number = {6}, year = {1995}, note = {

HartlKafatosO{\textquoteright}BrienENG1995/12/01Curr Opin Genet Dev. 1995 Dec 1;5(6):705-8.

}, month = {Dec 1}, pages = {705-8}, isbn = {1879-0380 (Electronic)0959-437X (Linking)}, author = {Hartl, D. L. and Kafatos, F. C. and O{\textquoteright}Brien, S. J.} } @article {539631, title = {Genomic regulation of transposable elements in Drosophila}, journal = {Curr Opin Genet Dev}, volume = {5}, number = {6}, year = {1995}, note = {

Lozovskaya, E RHartl, D LPetrov, D AengReviewENGLAND1995/12/01Curr Opin Genet Dev. 1995 Dec;5(6):768-73.

}, month = {Dec}, pages = {768-73}, abstract = {

Transposable elements are a major source of genetic change, including the creation of novel genes, the alteration of gene expression in development, and the genesis of major genomic rearrangements. They are ubiquitous among contemporary organisms and probably as old as life itself. The long coexistence of transposable elements in the genome would be expected to be accompanied by host-element coevolution. Indeed, the important role of host factors in the regulation of transposable elements has been illuminated by recent studies of several systems in Drosophila. These include host factors that regulate the P element, a host mutation that renders the genome permissive for gypsy mobilization and infection, and newly induced mutations that affect the expression of transposon insertion mutations. The finding of a type of hybrid dysgenesis in D. virilis, in which multiple unrelated transposable elements are mobilized simultaneously, may also be relevant to host-factor regulation of transposition.

}, keywords = {*DNA Transposable Elements, *Gene Expression Regulation, Animals, Chromosome Aberrations, Chromosome Disorders, Chromosome Mapping, Drosophila/*genetics, Genes, Insect, genome, Retroelements}, isbn = {0959-437X (Print)0959-437X (Linking)}, author = {Lozovskaya, E. R. and Hartl, D. L. and Petrov, D. A.} } @article {539611, title = {Genotypic effects, maternal effects and grand-maternal effects of immobilized derivatives of the transposable element mariner}, journal = {Genetics}, volume = {140}, number = {1}, year = {1995}, note = {

Lohe, A RLidholm, D AHartl, D LengGM-33741/GM/NIGMS NIH HHS/Comparative StudyResearch Support, U.S. Gov{\textquoteright}t, P.H.S.1995/05/01Genetics. 1995 May;140(1):183-92.

}, month = {May}, pages = {183-92}, abstract = {

The baseline rate of spontaneous integration of the autonomous mariner element Mos1 into the germline of Drosophila melanogaster is estimated as 16 +/- 5\% (mean +/- SE) among fertile G0 flies. However, the transformation rate is reduced approximately 20-fold in Mos1 constructs with exogenous DNA in the size range 5-12 kb inserted into the SacI site. To provide alternative Mos1 helper plasmids for transformation experiments, two types of Mos1-promoter fusions were constructed: hsp-70:Mos1 and hsp26-Sgs3:Mos1. The former has the Mos1 coding region driven by the hsp70 heat-shock promoter; the latter has it driven by the basal Sgs3 promoter under the control of the hsp26 female-germline specific transcriptional regulator. When introduced into D. melanogaster by P-element-mediated germline transformation, these elements are unable to transpose or excise in the presence of autonomous Mos1-related elements (they are "marooned") because the 5{\textquoteright} inverted repeat of Mos1 is missing. As expected, the hsp26-Sgs3:Mos1 fusions exhibit a significantly greater rate of germline excision of a target mariner element than do the hsp70:Mos1 fusions. Unexpectedly, the rate of excision of target mariner elements induced by hsp26-Sgs3:Mos1 is the same in the male germline as in the female germline. Both hsp:Mos1 fusions show strong germline expression and a maternal effect of the mariner transposase. A significant grand-maternal effect of the hsp:Mos1 fusions was also detected as a result of a maternal effect on the germline of the F1 progeny. Among flies carrying the promoter fusions inherited maternally, about three-quarters of the overall rate of germline excision derives from the direct genotypic effect and about one-quarter results from the grand-maternal effect. Despite the strong somatic expression of the hsp:Mos1 fusions, mariner transformants carrying a white+ reporter gene at the SacI site remained stable in the soma.

}, keywords = {Animals, DNA Transposable Elements/*genetics, Drosophila melanogaster/*genetics, Eye Color/genetics, Female, Genes, Insect, Genotype, Male, Mutagenesis, Insertional, Recombinant Fusion Proteins/genetics/metabolism, Repetitive Sequences, Nucleic Acid, Sequence Deletion, Transformation, Genetic}, isbn = {0016-6731 (Print)0016-6731 (Linking)}, author = {Lohe, A. R. and Lidholm, D. A. and Hartl, D. L.} } @article {539616, title = {Horizontal transmission, vertical inactivation, and stochastic loss of mariner-like transposable elements}, journal = {Mol Biol Evol}, volume = {12}, number = {1}, year = {1995}, note = {

Lohe, A RMoriyama, E NLidholm, D AHartl, D LengGM33741/GM/NIGMS NIH HHS/Research Support, Non-U.S. Gov{\textquoteright}tResearch Support, U.S. Gov{\textquoteright}t, P.H.S.1995/01/01Mol Biol Evol. 1995 Jan;12(1):62-72.

}, month = {Jan}, pages = {62-72}, abstract = {

Horizontal transmission has been well documented as a major mechanism for the dissemination of mariner-like elements (MLEs) among species. Less well understood are mechanisms that limit vertical transmission of MLEs resulting in the "spotty" or discontinuous distribution observed in closely related species. In this article we present evidence that the genome of the common ancestor of the melanogaster species subgroup of Drosophila contained an MLE related to the mellifera (honey bee) subfamily. Horizontal transmission, approximately 3-10 MYA, is strongly suggested by the observation that the sequence of the MLE in Drosophila erecta is 97\% identical in nucleotide sequence with that of an MLE in the cat flea, Ctenocephalides felis. The D. erecta MLE has a spotty distribution among species in the melanogaster subgroup. The element has a high copy number in D. erecta and D. orena, a moderate copy number in D. teissieri and D. yakuba, and was apparently lost ("stochastic loss") in the lineage leading to D. melanogaster, D. simulans, D. mauritiana, and D. sechellia. In D. erecta, most copies are concentrated in the heterochromatin. Two copies from D. erecta, denoted De12 and De19, were cloned and sequenced, and they appear to be nonfunctional ("vertical inactivation"). It therefore appears that the predominant mode of MLE evolution is vertical inactivation and stochastic loss balanced against occasional reinvasion of lineages by horizontal transmission.

}, keywords = {*Biological Evolution, *DNA Transposable Elements, Amino Acid Sequence, Animals, Blotting, Southern, Cats, DNA/analysis/genetics, Drosophila melanogaster/genetics, Drosophila/*genetics, Genetic Variation, In Situ Hybridization, Insects/*genetics, Molecular Sequence Data, Nucleotidyltransferases/chemistry/*genetics, Sequence Homology, Amino Acid, Siphonaptera/genetics, Stochastic Processes, Transposases}, isbn = {0737-4038 (Print)0737-4038 (Linking)}, author = {Lohe, A. R. and Moriyama, E. N. and Lidholm, D. A. and Hartl, D. L.} } @article {538796, title = {Opsin phylogeny and evolution: a model for blue shifts in wavelength regulation}, journal = {Mol Phylogenet Evol}, volume = {4}, number = {1}, year = {1995}, note = {

Chang, B SCrandall, K ACarulli, J PHartl, D Leng2R01 GM3157110/GM/NIGMS NIH HHS/Comparative StudyResearch Support, U.S. Gov{\textquoteright}t, P.H.S.1995/03/01Mol Phylogenet Evol. 1995 Mar;4(1):31-43.

}, month = {Mar}, pages = {31-43}, abstract = {

The vast diversity in spectral sensitivities in the vision of many organisms is mediated mostly (although not entirely) through variation in the photosensitive visual pigments (opsins) of the eye. Specifically, shifts in absorption maxima of visual pigments are thought to be a result of interactions within the binding pocket of the opsin, between amino acid side chains and the retinal chromophore, However, it has proven difficult to identify specific amino acid residues important in determining wavelength absorption maxima, especially for some of the short wavelength (blue) opsins. In this paper, a comparative phylogenetic approach was applied to opsin protein sequence data to identify residues important in opsin wavelength regulation. In essence, this approach consisted of interpreting evolutionary history as a series of experiments in which natural selection has repeatedly favored amino acid replacements of certain residues to shift the opsin absorption spectra to either shorter or longer wavelengths. Opsin protein sequences were obtained from GenBank, aligned, and used to reconstruct a phylogenetic tree. Amino acid replacements were traced along the branches of this opsin tree, focusing only on residues likely to reside within the chromophore-binding pocket. A number of functionally convergent, nonconservative amino acid replacements in independently evolved opsins with similar shifts in spectral properties were identified. In short, reconstruction of the phylogeny of the opsin molecule allowed us to track amino acid substitutions in specific sites within the opsin and to target those particular substitutions that are repeatedly associated with marked changes in peak absorbance, shifting the spectral sensitivity of the opsin toward shorter or longer wavelengths. Based on these results, we propose a model for blue shifts of opsin absorption spectra. Amino acid replacements of four polar and charged residues near the protonated Schiff base (SBH+) end of the chromophore are proposed to result in blue shifts of the opsin absorption spectra. This model may explain some of the diversity of blue opsins apparent in both vertebrates and invertebrates.

}, keywords = {*Phylogeny, Amino Acid Sequence, Animals, Biological Evolution, Invertebrates/genetics/metabolism, Light, Models, Molecular, Molecular Sequence Data, Mutation, Rod Opsins/chemistry/*genetics/radiation effects, Schiff Bases, Sequence Alignment, Sequence Homology, Amino Acid, Software, Structure-Activity Relationship, Vertebrates/genetics/metabolism}, isbn = {1055-7903 (Print)1055-7903 (Linking)}, author = {Chang, B. S. and Crandall, K. A. and Carulli, J. P. and Hartl, D. L.} } @article {540011, title = {P1 clones from Drosophila melanogaster as markers to study the chromosomal evolution of Muller{\textquoteright}s A element in two species of the obscura group of Drosophila}, journal = {Chromosoma}, volume = {104}, number = {2}, year = {1995}, note = {

Segarra, CLozovskaya, E RRibo, GAguade, MHartl, D LengResearch Support, Non-U.S. Gov{\textquoteright}tResearch Support, U.S. Gov{\textquoteright}t, P.H.S.GERMANY1995/11/01Chromosoma. 1995 Nov;104(2):129-36.

}, month = {Nov}, pages = {129-36}, abstract = {

Thirty P1 clones from the X chromosome (Muller{\textquoteright}s A element) of Drosophila melanogaster were cross-hybridized in situ to Drosophila subobscura and Drosophila pseudoobscura polytene chromosomes. An additional recombinant phage lambda Dsuby was also used as a marker. Twenty-three (77\%) of the P1 clones gave positive hybridization on D. pseudoobscura chromosomes but only 16 (53\%) did so with those of D. subobscura. Eight P1 clones gave more than one hybridization signal on D. pseudoobscura and/or D. subobscura chromosomes. All P1 clones and lambda Dsuby hybridized on Muller{\textquoteright}s A element (X chromosome) of D. subobscura. In contrast, only 18 P1 clones and lambda Dsuby hybridized on Muller{\textquoteright}s A element (XL chromosomal arm) of D. pseudoobscura; 4 additional P1 clones hybridized on Muller{\textquoteright}s D element (XR chromosomal arm) of this species and the remaining P1 clone gave one hybridization signal on each arm of the X chromosome. This latter clone may contain one breakpoint of a pericentric inversion that may account for the interchange of genetic material between Muller{\textquoteright}s A and D elements in D. pseudoobscura. In contrast to the rare interchange of genetic material between chromosomal elements, profound differences in the order and spacing of markers were detected between D. melanogaster, D. pseudoobscura and D. subobscura. In fact, the number of chromosomal segments delimited by identical markers and conserved between pairwise comparisons is small. Therefore, extensive reorganization within Muller{\textquoteright}s A element has been produced during the divergence of the three species. Rough estimates of the number of cytologically detectable inversions contributing to differentiation of Muller{\textquoteright}s A element were obtained. The most reliable of these estimates is that obtained from the D. pseudoobscura and D. melanogaster comparison since a greater number of markers have been mapped in both species. Tentatively, one inversion breakpoint about every 200 kb has been produced and fixed during the divergence of D. pseudoobscura and D. melanogaster.

}, keywords = {*Evolution, Molecular, *Genetic Markers, *X Chromosome, Animals, Chromosome Inversion, Chromosome Mapping/*methods, Cloning, Molecular, Drosophila melanogaster/genetics, Drosophila/classification/*genetics, In Situ Hybridization}, isbn = {0009-5915 (Print)0009-5915 (Linking)}, author = {Segarra, C. and Lozovskaya, E. R. and Ribo, G. and Aguade, M. and Hartl, D. L.} } @article {538531, title = {Genetic variation in IncI1-ColIb plasmids}, journal = {J Mol EvolJ Mol EvolJ Mol Evol}, volume = {39}, number = {2}, year = {1994}, note = {Ayala, F JKrane, D EHartl, D LengGM40322/GM/NIGMS NIH HHS/Comparative StudyResearch Support, U.S. Gov{\textquoteright}t, P.H.S.1994/08/01J Mol Evol. 1994 Aug;39(2):129-33.}, month = {Aug}, pages = {129-33}, abstract = {Nucleotide sequences of portions of three plasmid genes (cib, cir, and abi) present in IncI1-ColIb colicin plasmids obtained from strains of Salmonella typhimurium isolated in either 1974 (Barker strains) or between 1935 and 1941 (Murray strains) were examined along with sequences of the chromosomal gene for 6-phosphogluconate dehydrogenase (gnd). Our principal findings were: (1) The plasmid genes were virtually identical to those in IncI1-ColIb plasmids from E. coli, suggesting that Salmonella and E. coli share overlapping pools of these plasmids. (2) The plasmid genes were much less polymorphic than gnd or any other known chromosomal gene from Salmonella, further suggesting horizontal transfer with rapid transmission and turnover. (3) No characteristic differences were found in either the plasmid genes or the chromosomal gene between the 1974 isolates and the Murray strains, indicating that these plasmids have been stable for at least several decades. (4) There was an excess of amino-acid replacement polymorphisms, relative to synonymous polymorphisms, in the plasmid genes, which is consistent with the hypothesis of diversifying selection among colicin-producing plasmid families. (5) The abi (abortive infection) gene present in each of the plasmids contained two single-nucleotide insertions relative to the published sequence. These result in a putative abi protein of 114 amino acids instead of 89.}, keywords = {Bacteriocin Plasmids/*genetics, Base Sequence, DNA, Complementary, Gene Expression Regulation, Bacterial, Genetic Variation, Molecular Sequence Data, Plasmids/*genetics, Polymerase Chain Reaction, Salmonella typhimurium/*genetics, Sequence Alignment}, isbn = {0022-2844 (Print)0022-2844 (Linking)}, author = {Ayala, F. J. and Krane, D. E. and Hartl, D. L.} } @article {539296, title = {DNA fingerprinting}, journal = {Science}, volume = {266}, number = {5183}, year = {1994}, note = {

Hartl, D LLewontin, R CengCommentLetterNew York, N.Y.1994/10/14Science. 1994 Oct 14;266(5183):201; author reply 202-3.

}, month = {Oct 14}, pages = {201; author reply 202-3}, keywords = {*DNA Fingerprinting/standards, Genetics, Population, Humans, Jurisprudence}, isbn = {0036-8075 (Print)0036-8075 (Linking)}, author = {Hartl, D. L. and Lewontin, R. C.} } @article {539171, title = {Forensic DNA typing dispute}, journal = {Nature}, volume = {372}, number = {6505}, year = {1994}, note = {

Hartl, D LengCommentLetterENGLAND1994/12/01Nature. 1994 Dec 1;372(6505):398-9.

}, month = {Dec 1}, pages = {398-9}, keywords = {*DNA Fingerprinting, Continental Population Groups/genetics, Government Agencies, Humans, Statistics as Topic, United States}, isbn = {0028-0836 (Print)0028-0836 (Linking)}, author = {Hartl, D. L.} } @article {539316, title = {Genome evolution: between the nucleosome and the chromosome}, journal = {EXS}, volume = {69}, year = {1994}, note = {

Hartl, D LLozovskaya, E RengGM33741/GM/NIGMS NIH HHS/HG00750/HG/NHGRI NIH HHS/Research Support, U.S. Gov{\textquoteright}t, P.H.S.ReviewSWITZERLAND1994/01/01EXS. 1994;69:579-92.

}, pages = {579-92}, abstract = {

Intermediate between DNA sequences and broad patterns of karyotypic change there is a major gap in understanding genome structure and evolution. The gap is at the megabase level between genes and chromosomes. New methods for analyzing large DNA fragments cloned in yeast or bacterial vectors provide experimental access to genome evolution at the megabase level by enabling the assembly of megabase-size contiguous regions. Genome evolution at the megabase level can also be studied using high-resolution genetic maps. Rates and patterns of genome evolution in mammals (mouse versus humans) and Drosophila (D. virilis versus D. melanogaster) are compared and contrasted. Opportunities for research in genome evolution using the new technologies are enumerated and discussed.

}, keywords = {*Biological Evolution, *Genome, Animals, Chromosomes/*genetics, Drosophila melanogaster/genetics, Mammals/genetics, Nucleosomes/*genetics}, isbn = {1023-294X (Print)1023-294X (Linking)}, author = {Hartl, D. L. and Lozovskaya, E. R.} } @article {539346, title = {Genome structure and evolution in Drosophila: applications of the framework P1 map}, journal = {Proc Natl Acad Sci U S A}, volume = {91}, number = {15}, year = {1994}, note = {

Hartl, D LNurminsky, D IJones, R WLozovskaya, E RengHG00750/HG/NHGRI NIH HHS/Research Support, U.S. Gov{\textquoteright}t, P.H.S.1994/07/19Proc Natl Acad Sci U S A. 1994 Jul 19;91(15):6824-9.

}, month = {Jul 19}, pages = {6824-9}, abstract = {

Physical maps showing the relative locations of cloned DNA fragments in the genome are important resources for research in molecular genetics, genome analysis, and evolutionary biology. In addition to affording a common frame of reference for organizing diverse types of genetic data, physical maps also provide ready access to clones containing DNA sequences from any defined region of the genome. In this paper, we present a physical map of the genome of Drosophila melanogaster based on in situ hybridization with 2461 DNA fragments, averaging approximately 80 kilobase pairs each, cloned in bacteriophage P1. The map is a framework map in the sense that most putative overlaps between clones have not yet been demonstrated at the molecular level. Nevertheless, the framework map includes approximately 85\% of all genes in the euchromatic genome. A continuous physical map composed of sets of overlapping P1 clones (contigs), which together span most of the euchromatic genome, is currently being assembled by screening a library of 9216 P1 clones with single-copy genetic markers as well as with the ends of the P1 clones already assigned positions in the framework map. Because most P1 clones from D. melanogaster hybridize in situ with chromosomes from related species, the framework map also makes it possible to determine the genome maps of D. pseudoobscura and other species in the subgenus Sophophora. Likewise, a P1 framework map of D. virilis affords potential access to genome organization and evolution in the subgenus Drosophila.

}, keywords = {*Biological Evolution, *Chromosome Mapping, Animals, Cloning, Molecular, Drosophila/*genetics, In Situ Hybridization, Polymerase Chain Reaction}, isbn = {0027-8424 (Print)0027-8424 (Linking)}, author = {Hartl, D. L. and Nurminsky, D. I. and Jones, R. W. and Lozovskaya, E. R.} } @article {538716, title = {Horizontal transmission versus ancient origin: mariner in the witness box}, journal = {Genetica}, volume = {93}, number = {1-3}, year = {1994}, note = {

Capy, PLangin, TBigot, YBrunet, FDaboussi, M JPeriquet, GDavid, J RHartl, D LengGM33741/GM/NIGMS NIH HHS/Comparative StudyResearch Support, Non-U.S. Gov{\textquoteright}tResearch Support, U.S. Gov{\textquoteright}t, Non-P.H.S.Research Support, U.S. Gov{\textquoteright}t, P.H.S.ReviewNETHERLANDS1994/01/01Genetica. 1994;93(1-3):161-70.

}, pages = {161-70}, abstract = {

The transposable element mariner has been found in many species of Drosophilidae, several groups of Arthropods, and more recently in Platyhelminthes as well as in a phytopathogenic fungus. In the family Drosophilidae, the distribution of mariner among species shows many gaps, and its geographical distribution among endemic species is restricted to Asia and Africa. Among mariner elements in species within and outside the Drosophilidae, the similarities in nucleotide sequence and the amino acid sequence of the putative transposase reveal many phylogenetic inconsistencies compared with the conventional phylogeny of the host species. This paper discusses the contrasting hypotheses of horizontal transfer versus ancestral origin proposed to explain these results.

}, keywords = {*DNA Transposable Elements, Africa, Amino Acid Sequence, Animals, Arthropods/*genetics, Asia, Drosophilidae/*genetics, Insects/*genetics, Molecular Sequence Data, Nucleotidyltransferases/*genetics, Platyhelminths/*genetics, Retroelements, Retroviridae/genetics, Sequence Homology, Amino Acid, Transposases}, isbn = {0016-6707 (Print)0016-6707 (Linking)}, author = {Capy, P. and Langin, T. and Bigot, Y. and Brunet, F. and Daboussi, M. J. and Periquet, G. and David, J. R. and Hartl, D. L.} } @article {539351, title = {Inverse polymerase chain reaction}, journal = {Methods Mol Biol}, volume = {31}, year = {1994}, note = {

Hartl, D LOchman, HengGM40322/GM/NIGMS NIH HHS/GM40995/GM/NIGMS NIH HHS/HG00357/HG/NHGRI NIH HHS/Research Support, U.S. Gov{\textquoteright}t, P.H.S.ReviewClifton, N.J.1994/01/01Methods Mol Biol. 1994;31:187-96.

}, pages = {187-96}, keywords = {DNA Primers, DNA, Complementary/genetics, DNA, Recombinant/genetics, Polymerase Chain Reaction/*methods}, isbn = {1064-3745 (Print)1064-3745 (Linking)}, author = {Hartl, D. L. and Ochman, H.} } @article {538736, title = {Phylogeny and physiology of Drosophila opsins}, journal = {J Mol Evol}, volume = {38}, number = {3}, year = {1994}, note = {

Carulli, J PChen, D MStark, W SHartl, D LengEY07108/EY/NEI NIH HHS/EY07192/EY/NEI NIH HHS/HG00750/HG/NHGRI NIH HHS/Comparative StudyResearch Support, U.S. Gov{\textquoteright}t, Non-P.H.S.Research Support, U.S. Gov{\textquoteright}t, P.H.S.1994/03/01J Mol Evol. 1994 Mar;38(3):250-62.

}, month = {Mar}, pages = {250-62}, abstract = {

Phylogenetic and physiological methods were used to study the evolution of the opsin gene family in Drosophila. A phylogeny based on DNA sequences from 13 opsin genes including representatives from the two major subgenera of Drosophila shows six major, well-supported clades: The "blue opsin" clade includes all of the Rh1 and Rh2 genes and is separated into two distinct subclades of Rh1 sequences and Rh2 sequences; the ultraviolet opsin clade includes all Rh3 and Rh4 genes and bifurcates into separate Rh3 and Rh4 clades. The duplications that generated this gene family most likely took place before the evolution of the subgenera Drosophila and Sophophora and their component species groups. Numerous changes have occurred in these genes since the duplications, including the loss and/or gain of introns in the different genes and even within the Rh1 and Rh4 clades. Despite these changes, the spectral sensitivity of each of the opsins has remained remarkably fixed in a sample of four species representing two species groups in each of the two subgenera. All of the strains that were investigated had R1-6 (Rh1) spectral sensitivity curves that peaked at or near 480 nm, R7 (Rh3 and Rh4) peaks in the ultraviolet range, and ocellar (Rh2) peaks near 420 nm. Each of the four gene clades on the phylogeny exhibits very conservative patterns of amino acid replacement in domains of the protein thought to influence spectral sensitivity, reflecting strong constraints on the spectrum of light visible to Drosophila.

}, keywords = {*Phylogeny, Amino Acid Sequence, Animals, Base Sequence, DNA Primers/genetics, DNA/genetics, Drosophila/classification/*genetics/physiology, Electroretinography, Genes, Insect, Light, Molecular Sequence Data, Multigene Family, Photochemistry, Rod Opsins/*genetics/physiology/radiation effects, Sequence Homology, Amino Acid}, isbn = {0022-2844 (Print)0022-2844 (Linking)}, author = {Carulli, J. P. and Chen, D. M. and Stark, W. S. and Hartl, D. L.} } @article {539341, title = {Selection intensity for codon bias}, journal = {Genetics}, volume = {138}, number = {1}, year = {1994}, note = {

Hartl, D LMoriyama, E NSawyer, S AengGM-40322/GM/NIGMS NIH HHS/GM-44889/GM/NIGMS NIH HHS/Research Support, U.S. Gov{\textquoteright}t, Non-P.H.S.Research Support, U.S. Gov{\textquoteright}t, P.H.S.1994/09/01Genetics. 1994 Sep;138(1):227-34.

}, month = {Sep}, pages = {227-34}, abstract = {

The patterns of nonrandom usage of synonymous codons (codon bias) in enteric bacteria were analyzed. Poisson random field (PRF) theory was used to derive the expected distribution of frequencies of nucleotides differing from the ancestral state at aligned sites in a set of DNA sequences. This distribution was applied to synonymous nucleotide polymorphisms and amino acid polymorphisms in the gnd and putP genes of Escherichia coli. For the gnd gene, the average intensity of selection against disfavored synonymous codons was estimated as approximately 7.3 x 10(-9); this value is significantly smaller than the estimated selection intensity against selectively disfavored amino acids in observed polymorphisms (2.0 x 10(-8)), but it is approximately of the same order of magnitude. The selection coefficients for optimal synonymous codons estimated from PRF theory were consistent with independent estimates based on codon usage for threonine and glycine. Across 118 genes in E. coli and Salmonella typhimurium, the distribution of estimated selection coefficients, expressed as multiples of the effective population size, has a mean and standard deviation of 0.5 +/- 0.4. No significant differences were found in the degree of codon bias between conserved positions and replacement positions, suggesting that translational misincorporation is not an important selective constraint among synonymous polymorphic codons in enteric bacteria. However, across the first 100 codons of the genes, conserved amino acids with identical codons have significantly greater codon bias than that of either synonymous or nonidentical codons, suggesting that there are unique selective constraints, perhaps including mRNA secondary structures, in this part of the coding region.

}, keywords = {*Models, Genetic, *Selection, Genetic, Codon/*genetics, DNA, Bacterial/genetics, Escherichia coli/genetics, Genes, Bacterial, Poisson Distribution, Polymorphism, Genetic, Salmonella typhimurium/genetics}, isbn = {0016-6731 (Print)0016-6731 (Linking)}, author = {Hartl, D. L. and Moriyama, E. N. and Sawyer, S. A.} } @article {539776, title = {Amplification of the ends of DNA fragments cloned in bacteriophage P1}, journal = {Biotechniques}, volume = {15}, number = {2}, year = {1993}, note = {

Nurminsky, D IHartl, D LengHG00750-01/HG/NHGRI NIH HHS/Research Support, U.S. Gov{\textquoteright}t, P.H.S.1993/08/01Biotechniques. 1993 Aug;15(2):201-2, 206-8.

}, month = {Aug}, pages = {201-2, 206-8}, keywords = {*Cloning, Molecular, *Polymerase Chain Reaction, Bacteriophage P1/*genetics, Base Sequence, Molecular Sequence Data}, isbn = {0736-6205 (Print)0736-6205 (Linking)}, author = {Nurminsky, D. I. and Hartl, D. L.} } @article {539731, title = {Codon usage bias and base composition of nuclear genes in Drosophila}, journal = {Genetics}, volume = {134}, number = {3}, year = {1993}, note = {

Moriyama, E NHartl, D LengGM33741/GM/NIGMS NIH HHS/GM40322/GM/NIGMS NIH HHS/Research Support, Non-U.S. Gov{\textquoteright}tResearch Support, U.S. Gov{\textquoteright}t, P.H.S.1993/07/01Genetics. 1993 Jul;134(3):847-58.

}, month = {Jul}, pages = {847-58}, abstract = {

The nuclear genes of Drosophila evolve at various rates. This variation seems to correlate with codon-usage bias. In order to elucidate the determining factors of the various evolutionary rates and codon-usage bias in the Drosophila nuclear genome, we compared patterns of codon-usage bias with base compositions of exons and introns. Our results clearly show the existence of selective constraints at the translational level for synonymous (silent) sites and, on the other hand, the neutrality or near neutrality of long stretches of nucleotide sequence within noncoding regions. These features were found for comparisons among nuclear genes in a particular species (Drosophila melanogaster, Drosophila pseudoobscura and Drosophila virilis) as well as in a particular gene (alcohol dehydrogenase) among different species in the genus Drosophila. The patterns of evolution of synonymous sites in Drosophila are more similar to those in the prokaryotes than they are to those in mammals. If a difference in the level of expression of each gene is a main reason for the difference in the degree of selective constraint, the evolution of synonymous sites of Drosophila genes would be sensitive to the level of expression among genes and would change as the level of expression becomes altered in different species. Our analysis verifies these predictions and also identifies additional selective constraints at the translational level in Drosophila.

}, keywords = {*Base Composition, *Biological Evolution, *Codon, Animals, Cell Nucleus, Drosophila/*genetics, Genomic Library, Introns}, isbn = {0016-6731 (Print)0016-6731 (Linking)}, author = {Moriyama, E. N. and Hartl, D. L.} } @article {539646, title = {A combined molecular and cytogenetic approach to genome evolution in Drosophila using large-fragment DNA cloning}, journal = {Chromosoma}, volume = {102}, number = {4}, year = {1993}, note = {

Lozovskaya, E RPetrov, D AHartl, D LengHG00357/HG/NHGRI NIH HHS/HG00750/HG/NHGRI NIH HHS/Comparative StudyResearch Support, U.S. Gov{\textquoteright}t, P.H.S.GERMANY1993/03/01Chromosoma. 1993 Mar;102(4):253-66.

}, month = {Mar}, pages = {253-66}, abstract = {

Methods of genome analysis, including the cloning and manipulation of large fragments of DNA, have opened new strategies for uniting molecular evolutionary genetics with chromosome evolution. We have begun the development of a physical map of the genome of Drosophila virilis based on large DNA fragments cloned in bacteriophage P1. A library of 10,080 P1 clones with average insert sizes of 65.8 kb, containing approximately 3.7 copies of the haploid genome of D. virilis, has been constructed and characterized. Approximately 75\% of the clones have inserts exceeding 50 kb, and approximately 25\% have inserts exceeding 80 kb. A sample of 186 randomly selected clones was mapped by in situ hybridization with the salivary gland chromosomes. A method for identifying D. virilis clones containing homologs of D. melanogaster genes has also been developed using hybridization with specific probes obtained from D. melanogaster by means of the polymerase chain reaction. This method proved successful for nine of ten genes and resulted in the recovery of 14 clones. The hybridization patterns of a sample of P1 clones containing repetitive DNA were also determined. A significant fraction of these clones hybridizes to multiple euchromatic sites but not to the chromocenter, which is a pattern of hybridization that is very rare among clones derived from D. melanogaster. The materials and methods described will make it possible to carry out a direct study of molecular evolution at the level of chromosome structure and organization as well as at the level of individual genes.

}, keywords = {*Biological Evolution, Animals, Base Sequence, Chromosome Mapping, Chromosomes/ultrastructure, Cloning, Molecular, Cytogenetics, DNA, Ribosomal/genetics, DNA/*genetics, Drosophila melanogaster/genetics, Drosophila/*genetics, Gene Library, In Situ Hybridization, Molecular Biology, Molecular Sequence Data, Polymerase Chain Reaction, Repetitive Sequences, Nucleic Acid, Species Specificity}, isbn = {0009-5915 (Print)0009-5915 (Linking)}, author = {Lozovskaya, E. R. and Petrov, D. A. and Hartl, D. L.} } @article {538746, title = {Compositional heterogeneity and patterns of molecular evolution in the Drosophila genome}, journal = {Genetics}, volume = {134}, number = {3}, year = {1993}, note = {

Carulli, J PKrane, D EHartl, D LOchman, HengEY07108/EY/NEI NIH HHS/GM-48407/GM/NIGMS NIH HHS/HG00750/HG/NHGRI NIH HHS/Research Support, U.S. Gov{\textquoteright}t, P.H.S.1993/07/01Genetics. 1993 Jul;134(3):837-45.

}, month = {Jul}, pages = {837-45}, abstract = {

The rates and patterns of molecular evolution in many eukaryotic organisms have been shown to be influenced by the compartmentalization of their genomes into fractions of distinct base composition and mutational properties. We have examined the Drosophila genome to explore relationships between the nucleotide content of large chromosomal segments and the base composition and rate of evolution of genes within those segments. Direct determination of the G + C contents of yeast artificial chromosome clones containing inserts of Drosophila melanogaster DNA ranging from 140-340 kb revealed significant heterogeneity in base composition. The G + C content of the large segments studied ranged from 36.9\% G + C for a clone containing the hunchback locus in polytene region 85, to 50.9\% G + C for a clone that includes the rosy region in polytene region 87. Unlike other organisms, however, there was no significant correlation between the base composition of large chromosomal regions and the base composition at fourfold degenerate nucleotide sites of genes encompassed within those regions. Despite the situation seen in mammals, there was also no significant association between base composition and rate of nucleotide substitution. These results suggest that nucleotide sequence evolution in Drosophila differs from that of many vertebrates and does not reflect distinct mutational biases, as a function of base composition, in different genomic regions. Significant negative correlations between codon-usage bias and rates of synonymous site divergence, however, provide strong support for an argument that selection among alternative codons may be a major contributor to variability in evolutionary rates within Drosophila genomes.

}, keywords = {*Biological Evolution, *Genome, Animals, Base Composition, Chromosomes, Fungal, Codon, Drosophila melanogaster/*genetics, Gene Library, Sequence Analysis, DNA}, isbn = {0016-6731 (Print)0016-6731 (Linking)}, author = {Carulli, J. P. and Krane, D. E. and Hartl, D. L. and Ochman, H.} } @article {539291, title = {DNA fingerprinting report}, journal = {Science}, volume = {260}, number = {5107}, year = {1993}, note = {

Hartl, D LLewontin, R CengCommentLetterNew York, N.Y.1993/04/23Science. 1993 Apr 23;260(5107):473-4.

}, month = {Apr 23}, pages = {473-4}, keywords = {*DNA Fingerprinting, Continental Population Groups, Ethnic Groups, Genetics, Population, Humans, Probability}, isbn = {0036-8075 (Print)0036-8075 (Linking)}, author = {Hartl, D. L. and Lewontin, R. C.} } @article {538526, title = {Molecular drift of the bride of sevenless (boss) gene in Drosophila}, journal = {Mol Biol Evol}, volume = {10}, number = {5}, year = {1993}, note = {

Ayala, F JHartl, D LengGM40322/GM/NIGMS NIH HHS/Comparative StudyResearch Support, U.S. Gov{\textquoteright}t, P.H.S.1993/09/01Mol Biol Evol. 1993 Sep;10(5):1030-40.

}, month = {Sep}, pages = {1030-40}, abstract = {

DNA sequences were determined for three to five alleles of the bride-of-sevenless (boss) gene in each of four species of Drosophila. The product of boss is a transmembrane receptor for a ligand coded by the sevenless gene that triggers differentiation of the R7 photoreceptor cell in the compound eye. Population parameters affecting the rate and pattern of molecular evolution of boss were estimated from the multinomial configurations of nucleotide polymorphisms of synonymous codons. The time of divergence between D. melanogaster and D. simulans was estimated as approximately 1 Myr, that between D. teissieri and D. yakuba as approximately 0.75 Myr, and that between the two pairs of sibling species as approximately 2 Myr. (The boss genes themselves have estimated divergence times approximately 50\% greater than the species divergence times.) The effective size of the species was estimated as approximately 5 x 10(6), and the average mutation rate was estimated as 1-2 x 10(-9)/nucleotide/generation. The ratio of amino acid polymorphisms within species to fixed differences between species suggests that approximately 25\% of all possible single-step amino acid replacements in the boss gene product may be selectively neutral or nearly neutral. The data also imply that random genetic drift has been responsible for virtually all of the observed differences in the portion of the boss gene analyzed among the four species.

}, keywords = {*Drosophila Proteins, *Genes, Insect, *Receptors, Peptide, Alcohol Dehydrogenase/genetics, Alleles, Animals, Base Sequence, DNA/genetics, Drosophila melanogaster/genetics, Drosophila/classification/*genetics, Eye Proteins/*genetics, Gene Frequency, Membrane Glycoproteins/*genetics, Molecular Sequence Data, Phylogeny, Polymerase Chain Reaction, Selection, Genetic, Sequence Alignment, Sequence Homology, Nucleic Acid, Species Specificity}, isbn = {0737-4038 (Print)0737-4038 (Linking)}, author = {Ayala, F. J. and Hartl, D. L.} } @article {538521, title = {Molecular evolution of the Rh3 gene in Drosophila}, journal = {Genetica}, volume = {92}, number = {1}, year = {1993}, note = {

Ayala, F JChang, B SHartl, D LengComparative StudyNETHERLANDS1993/01/01Genetica. 1993;92(1):23-32.

}, pages = {23-32}, abstract = {

Previous investigations into the evolution of the Drosophila opsin gene family are extended by inter- and intraspecific DNA sequence comparisons of the Rh3 locus in the melanogaster subgroup and D. pseudoobscura. Two separate statistical tests of the neutral-mutation hypothesis suggest that random genetic drift is responsible for virtually all of the observed amino acid replacement substitutions within the melanogaster subgroup. Analyses incorporating the D. pseudoobscura sequences are enigmatic due to the accumulation of multiple substitutions, because the McDonald-Kreitman test is not applicable to species comparisons that approach mutational saturation. However, the data from D. pseudoobscura are not inconsistent with selective neutrality. The ratio of amino acid polymorphisms within species to fixed differences between species imply that there are approximately 31 possible neutral single-step amino-acid-replacement substitutions at this locus. Synonymous substitutions are unevenly distributed among the structural domains of the Rh3 gene. Patterns of synonymous polymorphism are analyzed with respect to GC content and codon bias, and are compared to other loci from the same species.

}, keywords = {*Biological Evolution, *Genes, Insect, Amino Acid Sequence, Animals, Base Composition, Codon, Computer Simulation, Drosophila melanogaster/genetics/metabolism, Drosophila/*genetics/metabolism, Female, Models, Genetic, Molecular Sequence Data, Polymorphism, Genetic, Rhodopsin/*genetics, Selection, Genetic, Sequence Alignment, Sequence Homology, Species Specificity}, isbn = {0016-6707 (Print)0016-6707 (Linking)}, author = {Ayala, F. J. and Chang, B. S. and Hartl, D. L.} } @article {539516, title = {Sequencing products of polymerase chain reaction}, journal = {Methods Enzymol}, volume = {218}, year = {1993}, note = {

Lawrence, J GHartl, D LOchman, Heng1993/01/01Methods Enzymol. 1993;218:26-35.

}, pages = {26-35}, keywords = {*Base Sequence, *Dna, DNA, Recombinant, Electrophoresis, Agar Gel/methods, Indicators and Reagents, Molecular Sequence Data, Oligodeoxyribonucleotides/isolation \& purification, Polymerase Chain Reaction/*methods, Templates, Genetic}, isbn = {0076-6879 (Print)0076-6879 (Linking)}, author = {Lawrence, J. G. and Hartl, D. L. and Ochman, H.} } @article {539581, title = {The transposable element mariner mediates germline transformation in Drosophila melanogaster}, journal = {Genetics}, volume = {134}, number = {3}, year = {1993}, note = {

Lidholm, D ALohe, A RHartl, D LengGM33741/GM/NIGMS NIH HHS/Research Support, Non-U.S. Gov{\textquoteright}tResearch Support, U.S. Gov{\textquoteright}t, P.H.S.1993/07/01Genetics. 1993 Jul;134(3):859-68.

}, month = {Jul}, pages = {859-68}, abstract = {

A vector for germline transformation in Drosophila melanogaster was constructed using the transposable element mariner. The vector, denoted pMlwB, contains a mariner element disrupted by an insertion containing the wild-type white gene from D. melanogaster, the beta-galactosidase gene from Escherichia coli and sequences that enable plasmid replication and selection in E. coli. The white gene is controlled by the promoter of the D. melanogaster gene for heat-shock protein 70, and the beta-galactosidase gene is flanked upstream by the promoter of the transposable element P as well as that of mariner. The MlwB element was introduced into the germline of D. melanogaster by co-injection into embryos with an active mariner element, Mos1, which codes for a functional transposase and serves as a helper. Two independent germline insertions were isolated and characterized. The results show that the MlwB element inserted into the genome in a mariner-dependent manner with the termini of the inverted repeats inserted at a TA dinucleotide. Both insertions exhibit an unexpected degree of germline and somatic stability, even in the presence of an active mariner element in the genetic background. These results demonstrate that the mariner transposable element, which is small (1286 bp) and relatively homogeneous in size among different copies, is nevertheless capable of promoting the insertion of the large (13.2 kb) MlwB element. Because of the widespread phylogenetic distribution of mariner among insects, these results suggest that mariner might provide a wide host-range transformation vector for insects.

}, keywords = {*DNA Transposable Elements, *Transformation, Genetic, Animals, Base Sequence, DNA/genetics, Drosophila melanogaster/embryology/*genetics, Female, Genotype, Germ Cells, Male, Molecular Sequence Data, Mosaicism, Plasmids}, isbn = {0016-6731 (Print)0016-6731 (Linking)}, author = {Lidholm, D. A. and Lohe, A. R. and Hartl, D. L.} } @article {539811, title = {Use of polymerase chain reaction to amplify segments outside boundaries of known sequences}, journal = {Methods Enzymol}, volume = {218}, year = {1993}, note = {

Ochman, HAyala, F JHartl, D LengComparative Study1993/01/01Methods Enzymol. 1993;218:309-21.

}, pages = {309-21}, keywords = {*Base Sequence, *Dna, Chromosome Walking, Chromosomes, Bacterial, DNA Transposable Elements, DNA, Recombinant, Escherichia coli/genetics, Indicators and Reagents, Mutagenesis, Insertional, Polymerase Chain Reaction/*methods}, isbn = {0076-6879 (Print)0076-6879 (Linking)}, author = {Ochman, H. and Ayala, F. J. and Hartl, D. L.} } @article {539311, title = {The Drosophila genome project: current status of the physical map}, journal = {Comp Biochem Physiol B}, volume = {103}, number = {1}, year = {1992}, note = {

Hartl, D LLozovskaya, E RengHG00357/HG/NHGRI NIH HHS/Research Support, U.S. Gov{\textquoteright}t, P.H.S.ReviewENGLAND1992/09/01Comp Biochem Physiol B. 1992 Sep;103(1):1-8.

}, month = {Sep}, pages = {1-8}, keywords = {*Chromosome Mapping, *Genome, Animals, Bacteriophage P1, Chromosomes, Fungal, Drosophila melanogaster/*genetics, Gene Library, Humans}, isbn = {0305-0491 (Print)0305-0491 (Linking)}, author = {Hartl, D. L. and Lozovskaya, E. R.} } @article {539526, title = {The evolution of insertion sequences within enteric bacteria}, journal = {Genetics}, volume = {131}, number = {1}, year = {1992}, note = {

Lawrence, J GOchman, HHartl, D LengGM 40322/GM/NIGMS NIH HHS/GM 40995/GM/NIGMS NIH HHS/Research Support, U.S. Gov{\textquoteright}t, P.H.S.1992/05/01Genetics. 1992 May;131(1):9-20.

}, month = {May}, pages = {9-20}, abstract = {

To identify mechanisms that influence the evolution of bacterial transposons, DNA sequence variation was evaluated among homologs of insertion sequences IS1, IS3 and IS30 from natural strains of Escherichia coli and related enteric bacteria. The nucleotide sequences within each class of IS were highly conserved among E. coli strains, over 99.7\% similar to a consensus sequence. When compared to the range of nucleotide divergence among chromosomal genes, these data indicate high turnover and rapid movement of the transposons among clonal lineages of E. coli. In addition, length polymorphism among IS appears to be far less frequent than in eukaryotic transposons, indicating that nonfunctional elements comprise a smaller fraction of bacterial transposon populations than found in eukaryotes. IS present in other species of enteric bacteria are substantially divergent from E. coli elements, indicating that IS are mobilized among bacterial species at a reduced rate. However, homologs of IS1 and IS3 from diverse species provide evidence that recombination events and horizontal transfer of IS among species have both played major roles in the evolution of these elements. IS3 elements from E. coli and Shigella show multiple, nested, intragenic recombinations with a distantly related transposon, and IS1 homologs from diverse taxa reveal a mosaic structure indicative of multiple recombination and horizontal transfer events.

}, keywords = {*DNA Transposable Elements, Base Sequence, Blotting, Southern, DNA, Bacterial/*genetics, Enterobacteriaceae/*genetics, Escherichia/genetics, Frameshift Mutation, Molecular Sequence Data, Open Reading Frames, Phylogeny, Polymerase Chain Reaction, Sequence Homology, Nucleic Acid, Serratia/genetics, Shigella/genetics}, isbn = {0016-6731 (Print)0016-6731 (Linking)}, author = {Lawrence, J. G. and Ochman, H. and Hartl, D. L.} } @article {538706, title = {Evolution of the transposable element mariner in the Drosophila melanogaster species group}, journal = {Genetica}, volume = {86}, number = {1-3}, year = {1992}, note = {

Capy, PDavid, J RHartl, D LengGM33741/GM/NIGMS NIH HHS/Research Support, Non-U.S. Gov{\textquoteright}tResearch Support, U.S. Gov{\textquoteright}t, P.H.S.NETHERLANDS1992/01/01Genetica. 1992;86(1-3):37-46.

}, pages = {37-46}, abstract = {

The population biology and molecular evolution of the transposable element mariner has been studied in the eight species of the melanogaster subgroup of the Drosophila subgenus Sophophora. The element occurs in D. simulans, D. mauritiana, D. sechellia, D. teissieri, and D. yakuba, but is not found in D. melanogaster, D. erecta, or D. orena. Sequence comparisons suggest that the mariner element was present in the ancestor of the species subgroup and was lost in some of the lineages. Most species contain both active and inactive mariner elements. A deletion of most of the 3{\textquoteright} end characterizes many elements in D. teissieri, but in other species the inactive elements differ from active ones only by simple nucleotide substitutions or small additions/deletions. Active mariner elements from all species are quite similar in nucleotide sequence, although there are some species-specific differences. Many, but not all, of the inactive elements are also quite closely related. The genome of D. mauritiana contains 20-30 copies of mariner, that of D. simulans 0-10, and that of D. sechellia only two copies (at fixed positions in the genome). The mariner situation in D. sechellia may reflect a reduced effective population size owing to the restricted geographical range of this species and its ecological specialization to the fruit of Morinda citrifolia.

}, keywords = {*DNA Transposable Elements, Alleles, Animals, Drosophila melanogaster/*genetics, Drosophila/classification/genetics, Phylogeny, Species Specificity}, isbn = {0016-6707 (Print)0016-6707 (Linking)}, author = {Capy, P. and David, J. R. and Hartl, D. L.} } @article {539446, title = {Genetic differences at four DNA typing loci in Finnish, Italian, and mixed Caucasian populations}, journal = {Proc Natl Acad Sci U S A}, volume = {89}, number = {22}, year = {1992}, note = {

Krane, D EAllen, R WSawyer, S APetrov, D AHartl, D LengComparative Study1992/11/15Proc Natl Acad Sci U S A. 1992 Nov 15;89(22):10583-7.

}, month = {Nov 15}, pages = {10583-7}, abstract = {

Highly polymorphic segments of the human genome containing variable numbers of tandem repeats (VNTRs) have been widely used to establish DNA profiles of individuals for use in forensics. Methods of estimating the probability of occurrence of matching DNA profiles between two randomly selected individuals have been subject to extensive debate regarding the possibility of significant substructure occurring within the major races. We have sampled two Caucasian subpopulations, Finns and Italians, at four commonly used VNTR loci to determine the extent to which the subgroups differ from each other and from a mixed Caucasian database. The data were also analyzed for the occurrence of linkage disequilibrium among the loci. The allele frequency distributions of some loci were found to differ significantly among the subpopulations in a manner consistent with population substructure. Major differences were also found in the probability of occurrence of matching DNA profiles between two individuals chosen at random from the same subpopulation. With respect to the Finnish and Italian subpopulations, the conventional product rule for estimating the probability of a multilocus VNTR match using a mixed Caucasian database consistently yields estimates that are artificially small. Systematic errors of this type were not found using the interim ceiling principle recently advocated in the National Research Council{\textquoteright}s report [National Research Council (1992) DNA Technology in Forensic Science (Natl. Acad. Sci., Washington)]. The interim ceiling principle is based on currently available racial or ethnic databases and sets an arbitrary lower limit on each VNTR allele frequency. In the future the ceiling frequencies are expected to be established from more adequate data acquired for relevant VNTR loci from multiple subpopulations.

}, keywords = {*European Continental Ancestry Group, *Genome, Human, *Polymorphism, Genetic, Alleles, Chromosomes, Human, DNA/*genetics, Finland/ethnology, Gene Frequency, Genetic Linkage, Humans, Italy/ethnology, Missouri, Probability, Repetitive Sequences, Nucleic Acid, Restriction Mapping}, isbn = {0027-8424 (Print)0027-8424 (Linking)}, author = {Krane, D. E. and Allen, R. W. and Sawyer, S. A. and Petrov, D. A. and Hartl, D. L.} } @article {539506, title = {Inference of horizontal genetic transfer from molecular data: an approach using the bootstrap}, journal = {Genetics}, volume = {131}, number = {3}, year = {1992}, note = {

Lawrence, J GHartl, D Leng40322/PHS HHS/Research Support, U.S. Gov{\textquoteright}t, P.H.S.1992/07/01Genetics. 1992 Jul;131(3):753-60.

}, month = {Jul}, pages = {753-60}, abstract = {

Inconsistencies in taxonomic relationships implicit in different sets of nucleic acid sequences potentially result from horizontal transfer of genetic material between genomes. A nonparametric method is proposed to determine whether such inconsistencies are statistically significant. A similarity coefficient is calculated from ranked pairwise identities and evaluated against a distribution of similarity coefficients generated from resampled data. Subsequent analyses of partial data sets, obtained by the elimination of individual taxa, identify particular taxa to which the significance may be attributed, and can sometimes help in distinguishing horizontal genetic transfer from inconsistencies due to convergent evolution or variation in evolutionary rate. The method was successfully applied to data sets that were not found to be significantly different with existing methods that use comparisons of phylogenetic trees. The new statistical framework is also applicable to the inference of horizontal transfer from restriction fragment length polymorphism distributions and protein sequences.

}, keywords = {*Phylogeny, *Transfection, Animals, Bacteria/classification/genetics, Drosophila/classification/genetics, Genetic techniques, Statistics as Topic/methods}, isbn = {0016-6731 (Print)0016-6731 (Linking)}, author = {Lawrence, J. G. and Hartl, D. L.} } @article {539321, title = {Nonautonomous transposable elements in prokaryotes and eukaryotes}, journal = {Genetica}, volume = {86}, number = {1-3}, year = {1992}, note = {

Hartl, D LLozovskaya, E RLawrence, J GengGM33741/GM/NIGMS NIH HHS/GM40322/GM/NIGMS NIH HHS/Research Support, U.S. Gov{\textquoteright}t, P.H.S.ReviewNETHERLANDS1992/01/01Genetica. 1992;86(1-3):47-53.

}, pages = {47-53}, abstract = {

Defective (nonautonomous) copies of transposable elements are relatively common in the genomes of eukaryotes but less common in the genomes of prokaryotes. With regard to transposable elements that exist exclusively in the form of DNA (nonretroviral transposable elements), nonautonomous elements may play a role in the regulation of transposition. In prokaryotes, plasmid-mediated horizontal transmission probably imposes a selection against nonautonomous elements, since nonautonomous elements are incapable of mobilizing themselves. The lower relative frequency of nonautonomous elements in prokaryotes may also reflect the coupling of transcription and translation, which may bias toward the cis activation of transposition. The cis bias we suggest need not be absolute in order to militate against the long-term maintenance of prokaryotic elements unable to transpose on their own. Furthermore, any cis bias in transposition would also decrease the opportunity for trans repression of transposition by nonautonomous elements.

}, keywords = {*DNA Transposable Elements/genetics, *Eukaryotic Cells, *Prokaryotic Cells, Animals, Bacteria/genetics, DNA/genetics, Drosophila melanogaster/genetics, Gene Expression Regulation, Genetics, Population, Models, Genetic, Multigene Family, Repetitive Sequences, Nucleic Acid}, isbn = {0016-6707 (Print)0016-6707 (Linking)}, author = {Hartl, D. L. and Lozovskaya, E. R. and Lawrence, J. G.} } @article {539166, title = {Population genetics of microbial organisms}, journal = {Curr Opin Genet Dev}, volume = {2}, number = {6}, year = {1992}, note = {

Hartl, D LengReviewENGLAND1992/12/01Curr Opin Genet Dev. 1992 Dec;2(6):937-42.

}, month = {Dec}, pages = {937-42}, abstract = {

Population data suggest that many parasitic protozoa (e.g. Trypanosoma, Leishmania, Entamoeba and Giardia) reproduce clonally, but this hypothesis has been highly controversial for Plasmodium falciparum. Although reproduction is predominantly clonal in the enteric bacteria Escherichia coli and Salmonella, the level of recombination affecting short (\< 1 kb) regions of the chromosome is sufficient such that many genes are obviously mosaics of different ancestries. Transposable insertion sequences in E. coli are examples of selfish DNA whose short-term population dynamics are determined mainly by transposition and horizontal transmission among strains balanced against the regulation of transposition as a function of copy number, and negative effects on fitness. Occasional advantageous effects of transposable elements have also been documented.

}, keywords = {Animals, Biological Evolution, DNA Transposable Elements, Enterobacteriaceae/classification/*genetics, Eukaryota/*genetics, Plasmids, Reproduction}, isbn = {0959-437X (Print)0959-437X (Linking)}, author = {Hartl, D. L.} } @article {539991, title = {Population genetics of polymorphism and divergence}, journal = {Genetics}, volume = {132}, number = {4}, year = {1992}, note = {

Sawyer, S AHartl, D LengGM30201/GM/NIGMS NIH HHS/GM33741/GM/NIGMS NIH HHS/GM44889/GM/NIGMS NIH HHS/etc.Comparative StudyResearch Support, U.S. Gov{\textquoteright}t, Non-P.H.S.Research Support, U.S. Gov{\textquoteright}t, P.H.S.1992/12/01Genetics. 1992 Dec;132(4):1161-76.

}, month = {Dec}, pages = {1161-76}, abstract = {

Frequencies of mutant sites are modeled as a Poisson random field in two species that share a sufficiently recent common ancestor. The selective effect of the new alleles can be favorable, neutral, or detrimental. The model is applied to the sample configurations of nucleotides in the alcohol dehydrogenase gene (Adh) in Drosophila simulans and Drosophila yakuba. Assuming a synonymous mutation rate of 1.5 x 10(-8) per site per year and 10 generations per year, we obtain estimates for the effective population size (N(e) = 6.5 x 10(6)), the species divergence time (tdiv = 3.74 million years), and an average selection coefficient (sigma = 1.53 x 10(-6) per generation for advantageous or mildly detrimental replacements), although it is conceivable that only two of the amino acid replacements were selected and the rest neutral. The analysis, which includes a sampling theory for the independent infinite sites model with selection, also suggests the estimate that the number of amino acids in the enzyme that are susceptible to favorable mutation is in the range 2-23 at any one time. The approach provides a theoretical basis for the use of a 2 x 2 contingency table to compare fixed differences and polymorphic sites with silent sites and amino acid replacements.

}, keywords = {*Genetics, Population, *Polymorphism, Genetic, Alcohol Dehydrogenase/genetics, Alleles, Animals, Base Sequence, Drosophila/*genetics, Mutation, Poisson Distribution, Sequence Alignment, Species Specificity}, isbn = {0016-6731 (Print)0016-6731 (Linking)}, author = {Sawyer, S. A. and Hartl, D. L.} } @article {538876, title = {A repetitive DNA element, associated with telomeric sequences in Drosophila melanogaster, contains open reading frames}, journal = {Chromosoma}, volume = {102}, number = {1}, year = {1992}, note = {

Danilevskaya, O NPetrov, D APavlova, M NKoga, AKurenova, E VHartl, D LengGERMANY1992/12/01Chromosoma. 1992 Dec;102(1):32-40.

}, month = {Dec}, pages = {32-40}, abstract = {

He-T sequences are a complex repetitive family of DNA sequences in Drosophila that are associated with telomeric regions, pericentromeric heterochromatin, and the Y chromosome. A component of the He-T family containing open reading frames (ORFs) is described. These ORF-containing elements within the He-T family are designated T-elements, since hybridization in situ with the polytene salivary gland chromosomes results in detectable signal exclusively at the chromosome tips. One T-element that has been sequenced includes ORFs of 1,428 and 1,614 bp. The ORFs are overlapping but one nucleotide out of frame with respect to each other. The longer ORF contains cysteine-histidine motifs strongly resembling nucleic acid binding domains of gag-like proteins, and the overall organization of the T-element ORFs is reminiscent of LINE elements. The T-elements are transcribed and appear to be conserved in Drosophila species related to D. melanogaster. The results suggest that T-elements may play a role in the structure and/or function of telomeres.

}, keywords = {*Repetitive Sequences, Nucleic Acid, Amino Acid Sequence, Animals, Base Sequence, Cloning, Molecular, DNA/genetics, Drosophila melanogaster/*genetics, Heterochromatin/ultrastructure, Male, Molecular Sequence Data, Open Reading Frames, Restriction Mapping, Sequence Homology, Amino Acid, Species Specificity, Telomere/ultrastructure, Transcription, Genetic, Y Chromosome/ultrastructure}, isbn = {0009-5915 (Print)0009-5915 (Linking)}, author = {Danilevskaya, O. N. and Petrov, D. A. and Pavlova, M. N. and Koga, A. and Kurenova, E. V. and Hartl, D. L.} } @article {539576, title = {Response}, journal = {Science}, volume = {255}, number = {5048}, year = {1992}, note = {

Lewontin, R CHartl, D LengNew York, N.Y.1992/02/28 00:00Science. 1992 Feb 28;255(5048):1053-4.

}, month = {Feb 28}, pages = {1053-4}, isbn = {0036-8075 (Print)0036-8075 (Linking)}, author = {Lewontin, R. C. and Hartl, D. L.} } @article {538711, title = {Sequence analysis of active mariner elements in natural populations of Drosophila simulans}, journal = {Genetics}, volume = {130}, number = {3}, year = {1992}, note = {

Capy, PKoga, ADavid, J RHartl, D LengGM33741/GM/NIGMS NIH HHS/Comparative StudyResearch Support, Non-U.S. Gov{\textquoteright}tResearch Support, U.S. Gov{\textquoteright}t, P.H.S.1992/03/01Genetics. 1992 Mar;130(3):499-506.

}, month = {Mar}, pages = {499-506}, abstract = {

Active and inactive mariner elements from natural and laboratory populations of Drosophila simulans were isolated and sequenced in order to assess their nucleotide variability and to compare them with previously isolated mariner elements from the sibling species Drosophila mauritiana and Drosophila sechellia. The active elements of D. simulans are very similar among themselves (average 99.7\% nucleotide identity), suggesting that the level of mariner expression in different natural populations is largely determined by position effects, dosage effects and perhaps other factors. Furthermore, the D. simulans elements exhibit nucleotide identities of 98\% or greater when compared with mariner elements from the sibling species. Parsimony analysis of mariner elements places active elements from the three species into separate groups and suggests that D. simulans is the species from which mariner elements in D. mauritiana and D. sechellia are most likely derived. This result strongly suggests that the ancestral form of mariner among these species was an active element. The two inactive mariner elements sequenced from D. simulans are very similar to the inactive peach element from D. mauritiana. The similarity may result from introgression between D. simulans and D. mauritiana or from selective constraints imposed by regulatory effects of inactive elements.

}, keywords = {*DNA Transposable Elements, Animals, Base Sequence, Biological Evolution, DNA, Drosophila/*genetics, Female, Male, Molecular Sequence Data, Phylogeny, Sequence Homology, Nucleic Acid}, isbn = {0016-6731 (Print)0016-6731 (Linking)}, author = {Capy, P. and Koga, A. and David, J. R. and Hartl, D. L.} } @article {539216, title = {Towards a Drosophila genome map}, journal = {Trends Genet}, volume = {8}, number = {2}, year = {1992}, note = {

Hartl, D LAjioka, J WCai, HLohe, A RLozovskaya, E RSmoller, D ADuncan, I WengHG00357/HG/NHGRI NIH HHS/Research Support, U.S. Gov{\textquoteright}t, P.H.S.ReviewENGLAND1992/02/01Trends Genet. 1992 Feb;8(2):70-5.

}, month = {Feb}, pages = {70-5}, abstract = {

A physical map of the genome of Drosophila melanogaster has been created using 965 yeast artificial chromosome (YAC) clones assigned to locations in the cytogenetic map by in situ hybridization with the polytene salivary gland chromosomes. Clones with insert sizes averaging about 200 kb, totaling 1.7 genome equivalents, have been mapped. More than 80\% of the euchromatic genome is included in the mapped clones, and 75\% of the euchromatic genome is included in 161 cytological contigs ranging in size up to 2.5 Mb (average size 510 kb). On the other hand, YAC coverage of the one-third of the genome constituting the heterochromatin is incomplete, and clones containing long tracts of highly repetitive simple satellite DNA sequences have not been recovered.

}, keywords = {*Chromosome Mapping, *Genome, Animals, Drosophila melanogaster/*genetics}, isbn = {0168-9525 (Print)0168-9525 (Linking)}, author = {Hartl, D. L. and Ajioka, J. W. and Cai, H. and Lohe, A. R. and Lozovskaya, E. R. and Smoller, D. A. and Duncan, I. W.} } @article {538741, title = {Variable rates of evolution among Drosophila opsin genes}, journal = {Genetics}, volume = {132}, number = {1}, year = {1992}, note = {

Carulli, J PHartl, D LengEY07108/EY/NEI NIH HHS/GM33741/GM/NIGMS NIH HHS/HG00357/HG/NHGRI NIH HHS/Comparative StudyResearch Support, U.S. Gov{\textquoteright}t, P.H.S.1992/09/01Genetics. 1992 Sep;132(1):193-204.

}, month = {Sep}, pages = {193-204}, abstract = {

DNA sequences and chromosomal locations of four Drosophila pseudoobscura opsin genes were compared with those from Drosophila melanogaster, to determine factors that influence the evolution of multigene families. Although the opsin proteins perform the same primary functions, the comparisons reveal a wide range of evolutionary rates. Amino acid identities for the opsins range from 90\% for Rh2 to more than 95\% for Rh1 and Rh4. Variation in the rate of synonymous site substitution is especially striking: the major opsin, encoded by the Rh1 locus, differs at only 26.1\% of synonymous sites between D. pseudoobscura and D. melanogaster, while the other opsin loci differ by as much as 39.2\% at synonymous sites. Rh3 and Rh4 have similar levels of synonymous nucleotide substitution but significantly different amounts of amino acid replacement. This decoupling of nucleotide substitution and amino acid replacement suggests that different selective pressures are acting on these similar genes. There is significant heterogeneity in base composition and codon usage bias among the opsin genes in both species, but there are no consistent relationships between these factors and the rate of evolution of the opsins. In addition to exhibiting variation in evolutionary rates, the opsin loci in these species reveal rearrangements of chromosome elements.

}, keywords = {*Biological Evolution, Amino Acid Sequence, Animals, Base Composition, Base Sequence, Chromosome Mapping, Cloning, Molecular, Codon/genetics, DNA, Drosophila melanogaster/*genetics, Drosophila/*genetics, Genomic Library, Molecular Sequence Data, Nucleotides/analysis, Rod Opsins/*genetics, Sequence Homology, Amino Acid, Sequence Homology, Nucleic Acid, Species Specificity}, isbn = {0016-6731 (Print)0016-6731 (Linking)}, author = {Carulli, J. P. and Hartl, D. L.} } @article {539361, title = {What did Gregor Mendel think he discovered?}, journal = {Genetics}, volume = {131}, number = {2}, year = {1992}, note = {

Hartl, D LOrel, VengBiographyHistorical Article1992/06/01Genetics. 1992 Jun;131(2):245-53.

}, month = {Jun}, pages = {245-53}, keywords = {Crosses, Genetic, Genetics/*history, Germany, History, 19th Century, Hybridization, Genetic, Plants/genetics, Scientific Misconduct, Statistics as Topic}, isbn = {0016-6731 (Print)0016-6731 (Linking)}, author = {Hartl, D. L. and Orel, V.} } @article {540036, title = {Characterization of bacteriophage P1 library containing inserts of Drosophila DNA of 75-100 kilobase pairs}, journal = {Chromosoma}, volume = {100}, number = {8}, year = {1991}, note = {

Smoller, D APetrov, DHartl, D Leng00357/PHS HHS/Research Support, U.S. Gov{\textquoteright}t, P.H.S.GERMANY1991/09/01Chromosoma. 1991 Sep;100(8):487-94.

}, month = {Sep}, pages = {487-94}, abstract = {

A multiple-hit bacteriophage P1 library containing DNA fragments from Drosophila melanogaster in the size range 75-100 kb was created and subjected to a preliminary evaluation for completeness, randomness, fidelity, and clone stability. This P1 library presently contains 3840 individual clones, or approximately two genome equivalents. The library was screened with a small set of unique-sequence test probes, and clones containing the sequences have been recovered. In situ hybridization with salivary gland chromosomes indicates that the clones originate from the site of the probe sequences in the genome, and filter hybridization of restriction digests suggests that the clones are not rearranged in comparison with the genomic sequences. Approximately 1.7\% of the clones contain sequences that hybridize with ribosomal DNA. A small subset of these clones was tested for stability by examination of restriction fragments produced after repeated subculturing, and no evidence for instability was found. The P1 cloning system has general utility in molecular genetics and may provide an important intermediate level of resolution in physical mapping of the Drosophila genome.

}, keywords = {*Gene Library, Animals, Bacteriophages/*genetics, Base Sequence, Chromosome Walking, Cloning, Molecular/methods, DNA, Drosophila melanogaster/*genetics, Electrophoresis, Genes, Viral, Molecular Sequence Data, Nucleic Acid Hybridization}, isbn = {0009-5915 (Print)0009-5915 (Linking)}, author = {Smoller, D. A. and Petrov, D. and Hartl, D. L.} } @article {538501, title = {Drosophila genome project: one-hit coverage in yeast artificial chromosomes}, journal = {Chromosoma}, volume = {100}, number = {8}, year = {1991}, note = {

Ajioka, J WSmoller, D AJones, R WCarulli, J PVellek, A EGarza, DLink, A JDuncan, I WHartl, D Leng00357/PHS HHS/Research Support, U.S. Gov{\textquoteright}t, P.H.S.GERMANY1991/09/01Chromosoma. 1991 Sep;100(8):495-509.

}, month = {Sep}, pages = {495-509}, abstract = {

We present a strategy for assembling a physical map of the genome of Drosophila melanogaster based on yeast artificial chromosomes (YACs). In this paper we report 500 YACs containing inserts of Drosophila DNA averaging 200 kb that have been assigned positions on the physical map by means of in situ hybridization with salivary gland chromosomes. The cloned DNA fragments have randomly sheared ends (DY clones) or ends generated by partial digestion with either NotI (N clones) or EcoRI (E clones). Relative to the euchromatic portion of the genome, the size distribution and genomic positions of the clones reveal no significant bias in the completeness or randomness of genome coverage. The 500 mapped euchromatic clones contain an aggregate of approximately 100 million base pairs of DNA, which is approximately one genome equivalent of Drosophila euchromatin.

}, keywords = {Animals, Chromosome Mapping/*methods, Chromosomes, Fungal, Cloning, Molecular, Drosophila melanogaster/*genetics, Gene Library, Nucleic Acid Hybridization}, isbn = {0009-5915 (Print)0009-5915 (Linking)}, author = {Ajioka, J. W. and Smoller, D. A. and Jones, R. W. and Carulli, J. P. and Vellek, A. E. and Garza, D. and Link, A. J. and Duncan, I. W. and Hartl, D. L.} } @article {539671, title = {Evidence for interspecific transfer of the transposable element mariner between Drosophila and Zaprionus}, journal = {J Mol Evol}, volume = {33}, number = {6}, year = {1991}, note = {

Maruyama, KHartl, D LengGM33741/GM/NIGMS NIH HHS/Research Support, U.S. Gov{\textquoteright}t, P.H.S.1991/12/01J Mol Evol. 1991 Dec;33(6):514-24.

}, month = {Dec}, pages = {514-24}, abstract = {

The transposable element mariner occurs widely in the melanogaster species group of Drosophila. However, in drosophilids outside of the melanogaster species group, sequences showing strong DNA hybridization with mariner are found only in the genus Zaprionus. The mariner sequence obtained from Zaprionus tuberculatus is 97\% identical with that from Drosophila mauritiana, a member of the melanogaster species subgroup, whereas a mariner sequence isolated from Drosophila tsacasi is only 92\% identical with that from D. mauritiana. Because D. tsacasi is much more closely related to D. mauritiana than is Zaprionus, the presence of mariner in Zaprionus may result from horizontal transfer. In order to confirm lack of a close phylogenetic relationship between the genus Zaprionus and the melanogaster species group, we compared the alcohol dehydrogenase (Adh) sequences among these species. The results show that the coding region of Adh is only 82\% identical between Z. tuberculatus and D. mauritiana, as compared with 90\% identical between D. tsacasi and D. mauritiana. Furthermore, the mariner gene phylogeny obtained by maximum likelihood and maximum parsimony analyses is discordant with the species phylogeny estimated by using the Adh genes. The only inconsistency in the mariner gene phylogeny is in the placement of the Zaprionus mariner sequence, which clusters with mariner from Drosophila teissieri and Drosophila yakuba in the melanogaster species subgroup. These results strongly suggest horizontal transfer.

}, keywords = {*DNA Transposable Elements, Alcohol Dehydrogenase/genetics, Animals, Base Sequence, Biological Evolution, Diptera/enzymology/*genetics, DNA, Drosophila/enzymology/*genetics, Molecular Sequence Data, Phylogeny, Sequence Homology, Nucleic Acid}, isbn = {0022-2844 (Print)0022-2844 (Linking)}, author = {Maruyama, K. and Hartl, D. L.} } @article {539676, title = {Evolution of the transposable element mariner in Drosophila species}, journal = {Genetics}, volume = {128}, number = {2}, year = {1991}, note = {

Maruyama, KHartl, D LengGM33741/GM/NIGMS NIH HHS/Research Support, U.S. Gov{\textquoteright}t, P.H.S.1991/06/01Genetics. 1991 Jun;128(2):319-29.

}, month = {Jun}, pages = {319-29}, abstract = {

The distribution of the transposable element mariner was examined in the genus Drosophila. Among the eight species comprising the melanogaster species subgroup, the element is present in D. mauritiana, D. simulans, D. sechellia, D. yakuba and D. teissieri, but it is absent in D. melanogaster, D. erecta and D. orena. Multiple copies of mariner were sequenced from each species in which the element occurs. The inferred phylogeny of the elements and the pattern of divergence were examined in order to evaluate whether horizontal transfer among species or stochastic loss could better account for the discontinuous distribution of the element among the species. The data suggest that the element was present in the ancestral species before the melanogaster subgroup diverged and was lost in the lineage leading to D. melanogaster and the lineage leading to D. erecta and D. orena. This inference is consistent with the finding that mariner also occurs in members of several other species subgroups within the overall melanogaster species group. Within the melanogaster species subgroup, the average divergence of mariner copies between species was lower than the coding region of the alcohol dehydrogenase (Adh) gene. However, the divergence of mariner elements within species was as great as that observed for Adh. We conclude that the relative sequence homogeneity of mariner elements within species is more likely a result of rapid amplification of a few ancestral elements than of concerted evolution. The mariner element may also have had unequal mutation rates in different lineages.

}, keywords = {*Biological Evolution, *DNA Transposable Elements, Animals, Base Sequence, Blotting, Southern, Cloning, Molecular, DNA, Drosophila melanogaster/*genetics, Drosophila/genetics, Genetic Variation, Molecular Sequence Data, Phylogeny, Restriction Mapping, Sequence Alignment}, isbn = {0016-6731 (Print)0016-6731 (Linking)}, author = {Maruyama, K. and Hartl, D. L.} } @article {538871, title = {He-T family DNA sequences in the Y chromosome of Drosophila melanogaster share homology with the X-linked stellate genes}, journal = {Chromosoma}, volume = {100}, number = {2}, year = {1991}, note = {

Danilevskaya, O NKurenova, E VPavlova, M NBebehov, D VLink, A JKoga, AVellek, AHartl, D LengResearch Support, U.S. Gov{\textquoteright}t, Non-P.H.S.GERMANY1991/02/01Chromosoma. 1991 Feb;100(2):118-24.

}, month = {Feb}, pages = {118-24}, abstract = {

The genome of Drosophila melanogaster contains a class of repetitive DNA sequences called the He-T family, which is unusual in being confined to telomeric and heterochromatic regions. The specific He-T fragment designated Dm665 was cloned in yeast by selection for an autonomously replicating sequence (ARS). Dm665 contains a restriction fragment length polymorphism (RFLP) that is specific to males and thus derives from the Y chromosome. Deletion mapping using X-Y translocations indicates that sequences homologous to Dm665 occur in at least one major cluster in each arm of the Y chromosome. Among 20 yeast artificial chromosome (YAC) clones containing Drosophila sequences homologous with Dm665, four clones derive from defined regions of the long arm of the Y and two from the short arm. The sequence of Dm665 is 2443 bp long, consists of 59\% A + T, and contains no significant open reading frames or direct or inverted repeats. However, Dm665 contains a region of 650 bp that shares homology with portions of the X-linked locus Stellate.

}, keywords = {*Dna, *Repetitive Sequences, Nucleic Acid, *Sequence Homology, Nucleic Acid, *X Chromosome, *Y Chromosome, Animals, Base Composition, Base Sequence, Chromosomes, Fungal, Cloning, Molecular, Drosophila/*genetics, Female, Gene Library, Male, Molecular Sequence Data, Nucleic Acid Hybridization, Plasmids, Polymorphism, Restriction Fragment Length}, isbn = {0009-5915 (Print)0009-5915 (Linking)}, author = {Danilevskaya, O. N. and Kurenova, E. V. and Pavlova, M. N. and Bebehov, D. V. and Link, A. J. and Koga, A. and Vellek, A. and Hartl, D. L.} } @article {539681, title = {Identification of nucleotide substitutions necessary for trans-activation of mariner transposable elements in Drosophila: analysis of naturally occurring elements}, journal = {Genetics}, volume = {128}, number = {4}, year = {1991}, note = {

Maruyama, KSchoor, K DHartl, D LengGM33741/GM/NIGMS NIH HHS/Research Support, U.S. Gov{\textquoteright}t, P.H.S.1991/08/01Genetics. 1991 Aug;128(4):777-84.

}, month = {Aug}, pages = {777-84}, abstract = {

Six copies of the mariner element from the genomes of Drosophila mauritiana and Drosophila simulans were chosen at random for DNA sequencing and functional analysis and compared with the highly active element Mos1 and the inactive element peach. All elements were 1286 base pairs in length, but among them there were 18 nucleotide differences. As assayed in Drosophila melanogaster, three of the elements were apparently nonfunctional, two were marginally functional, and one had moderate activity that could be greatly increased depending on the position of the element in the genome. Both molecular (site-directed mutagenesis) and evolutionary (cladistic analysis) techniques were used to analyze the functional effects of nucleotide substitutions. The nucleotide sequence of the element is the primary determinant of function, though the activity level of elements is profoundly influenced by position effects. Cladistic analysis of the sequences has identified a T----A transversion at position 1203 (resulting in a Phe----Leu amino acid replacement in the putative transposase) as being primarily responsible for the low activity of the barely functional elements. Use of the sequences from the more distantly related species, Drosophila yakuba and Drosophila teissieri, as outside reference species, indicates that functional mariner elements are ancestral and argues against their origination by a novel mutation or by recombination among nonfunctional elements.

}, keywords = {*DNA Transposable Elements, *Transcriptional Activation, Animals, Base Sequence, Cloning, Molecular, DNA Mutational Analysis, Drosophila/*genetics, Genetic Vectors, Molecular Sequence Data, Mosaicism, Mutagenesis, Site-Directed, Phylogeny, Transformation, Genetic}, isbn = {0016-6731 (Print)0016-6731 (Linking)}, author = {Maruyama, K. and Schoor, K. D. and Hartl, D. L.} } @article {538721, title = {Insertion sites of the transposable element mariner are fixed in the genome of Drosophila sechellia}, journal = {J Mol Evol}, volume = {33}, number = {5}, year = {1991}, note = {

Capy, PMaruyama, KDavid, J RHartl, D LengGM33741/GM/NIGMS NIH HHS/Comparative StudyResearch Support, Non-U.S. Gov{\textquoteright}tResearch Support, U.S. Gov{\textquoteright}t, P.H.S.1991/11/01J Mol Evol. 1991 Nov;33(5):450-6.

}, month = {Nov}, pages = {450-6}, abstract = {

The abundance of the transposable element mariner differs dramatically in the genomes of the closely related species Drosophila simulans, D. mauritiana, D. sechellia, and D. melanogaster. Natural populations of D. simulans and D. mauritiana have 1-10 and 20-30 copies per diploid genome, respectively, and the insertion sites are polymorphic. The element has not been found in D. melanogaster. In this paper we show that D. sechellia, a species endemic to the Seychelles Islands, contains only two mariner elements that are at fixed sites in the genome. One element, inserted in chromosome 2R at 51A1-2, contains three deletions and is missing much of the 3{\textquoteright} end. The other element, inserted in chromosome 3L at 64A10-11, is the full length of 1286 bp. Although the sequence of the full-length element is polymorphic in populations of D. sechellia, at least some of the sequences are closely related to elements from D. simulans and D. mauritiana that are known to be active. However, judging from the progeny of crosses between D. sechellia and D. simulans, the biological activity of the full-length D. sechellia element appears to be low, either because of the nucleotide sequence of the element or because of its position in the genome, or both.

}, keywords = {*Biological Evolution, *DNA Transposable Elements, *Genome, Animals, Base Sequence, Blotting, Southern, DNA/genetics/isolation \& purification, Drosophila/*genetics, Molecular Sequence Data, Oligodeoxyribonucleotides, Polymerase Chain Reaction, Restriction Mapping, Salivary Glands/cytology, Software}, isbn = {0022-2844 (Print)0022-2844 (Linking)}, author = {Capy, P. and Maruyama, K. and David, J. R. and Hartl, D. L.} } @article {539016, title = {Introduction of the transposable element mariner into the germline of Drosophila melanogaster}, journal = {Genetics}, volume = {128}, number = {2}, year = {1991}, note = {

Garza, DMedhora, MKoga, AHartl, D LengGM33741/GM/NIGMS NIH HHS/Research Support, U.S. Gov{\textquoteright}t, P.H.S.1991/06/01Genetics. 1991 Jun;128(2):303-10.

}, month = {Jun}, pages = {303-10}, abstract = {

A chimeric white gene (wpch) and other constructs containing the transposable element mariner from Drosophila mauritiana were introduced into the germline of Drosophila melanogaster using transformation mediated by the P element. In the absence of other mariner elements, the wpch allele is genetically stable in both germ cells and somatic cells, indicating that the peach element (i.e., the particular copy of mariner inserted in the wpch allele) is inactive. However, in the presence of the active element Mos1, the wpch allele reverts, owing to excision of the peach element, yielding eye-color mosaics and a high rate of germline reversion. In strains containing Mos1 virtually every fly is an eye-color mosaic, and the rate of wpch germline reversion ranges from 10 to 25\%, depending on temperature. The overall rates of mariner excision and transposition are approximately sixfold greater than the rates in comparable strains of Drosophila simulans. The activity of the Mos1 element is markedly affected by position effects at the site of Mos1 insertion. In low level mosiac lines, dosage effects of Mos1 are apparent in the heavier level of eye-color mosaicism in Mos1 homozygotes than in heterozygotes. However, saturation occurs in high level mosaic lines, and then dosage effects are not observed. A pBluescribe M13+ plasmid containing Mos1 was injected into the pole plasm of D. melanogaster embryos, and the Mos1 element spontaneously integrated into the germline at high efficiency. These transformed strains of D. melanogaster presently contain numerous copies of mariner and may be useful in transposon tagging and other applications.

}, keywords = {*DNA Transposable Elements, *Germ Cells, *Transformation, Genetic, Alleles, Animals, Drosophila melanogaster/*genetics, Eye Color/genetics, Mosaicism/genetics, Temperature}, isbn = {0016-6731 (Print)0016-6731 (Linking)}, author = {Garza, D. and Medhora, M. and Koga, A. and Hartl, D. L.} } @article {539521, title = {Molecular and evolutionary relationships among enteric bacteria}, journal = {J Gen Microbiol}, volume = {137}, number = {8}, year = {1991}, note = {

Lawrence, J GOchman, HHartl, D LengGM 40322/GM/NIGMS NIH HHS/GM 40995/GM/NIGMS NIH HHS/Research Support, U.S. Gov{\textquoteright}t, P.H.S.ENGLAND1991/08/01J Gen Microbiol. 1991 Aug;137(8):1911-21.

}, month = {Aug}, pages = {1911-21}, abstract = {

Classification of bacterial species into genera has traditionally relied upon variation in phenotypic characteristics. However, these phenotypes often have a multifactorial genetic basis, making unambiguous taxonomic placement of new species difficult. By designing evolutionarily conserved oligonucleotide primers, it is possible to amplify homologous regions of genes in diverse taxa using the polymerase chain reaction and determine their nucleotide sequences. We have constructed a phylogeny of some enteric bacteria, including five species classified as members of the genus Escherichia, based on nucleotide sequence variation at the loci encoding glyceraldehyde-3-phosphate dehydrogenase and outer membrane protein 3A, and compared this genealogy with the relationships inferred by biotyping. The DNA sequences of these genes defined congruent and robust phylogenetic trees indicating that they are an accurate reflection of the evolutionary history of the bacterial species. The five species of Escherichia were found to be distantly related and, contrary to their placement in the same genus, do not form a monophyletic group. These data provide a framework which allows the relationships of additional species of enteric bacteria to be inferred. These procedures have general applicability for analysis of the classification, evolution, and epidemiology of bacterial taxa.

}, keywords = {*Biological Evolution, Bacterial Outer Membrane Proteins/*genetics, Bacterial Typing Techniques, Base Sequence, Enterobacteriaceae/classification/*genetics, Escherichia coli/classification/*genetics, Glyceraldehyde-3-Phosphate Dehydrogenases/*genetics, Molecular Sequence Data, Oligonucleotides/genetics, Phenotype, Phylogeny, Polymerase Chain Reaction, Sequence Alignment}, isbn = {0022-1287 (Print)0022-1287 (Linking)}, author = {Lawrence, J. G. and Ochman, H. and Hartl, D. L.} } @article {539691, title = {Molecular and functional analysis of the mariner mutator element Mos1 in Drosophila}, journal = {Genetics}, volume = {128}, number = {2}, year = {1991}, note = {

Medhora, MMaruyama, KHartl, D LengGM33741/GM/NIGMS NIH HHS/Research Support, U.S. Gov{\textquoteright}t, P.H.S.1991/06/01Genetics. 1991 Jun;128(2):311-8.

}, month = {Jun}, pages = {311-8}, abstract = {

The white-peach allele in Drosophila results from insertion of the transposable element mariner. The particular copy that is inserted in white-peach is an inactive copy referred to as the peach element. The peach element is excised at a high rate in the presence of active copies of mariner located elsewhere in the genome, and the excision of peach in somatic cells is recognized phenotypically by the occurrence of eye-color mosaicism in white-peach flies. Active mariner elements identified by their ability to induce high levels of white-peach mosaicism are denoted Mos (Mosaic) factors. We have sequenced and functionally analyzed the factor Mos1 originally identified in Drosophila mauritiana. The Mos1 element is 1286 base pairs in length, the same length as the peach element. It differs from the peach element in 11 nucleotide positions distributed throughout its length, including four amino acid replacements in the long open reading frame. Analysis of chimeric constructs between Mos1 and peach implies that functionally important differences occur in both the 5{\textquoteright} and 3{\textquoteright} halves of Mos1. A mariner element identical in sequence to Mos1 yields lower levels of mosaicism in transformants, implying that adjacent flanking sequences have important effects on Mos1 activity. Another mariner element, designated Ma351, isolated from a nonmosaic strain of D. mauritiana, differs from Mos1 in just three nucleotide positions. When introduced into the germline, Ma351 yields various levels of white-peach mosaicism depending on insertion site. These results imply that the activity of mariner elements is determined jointly by their own nucleotide sequences, by the effects of adjacent flanking sequences, and by longer-range position effects.

}, keywords = {*DNA Transposable Elements, *Mutation, Amino Acid Sequence, Animals, Base Sequence, Chimera/genetics, Cloning, Molecular, DNA, Drosophila/*genetics, Female, Male, Molecular Sequence Data, Phenotype, Restriction Mapping}, isbn = {0016-6731 (Print)0016-6731 (Linking)}, author = {Medhora, M. and Maruyama, K. and Hartl, D. L.} } @article {539511, title = {Molecular considerations in the evolution of bacterial genes}, journal = {J Mol Evol}, volume = {33}, number = {3}, year = {1991}, note = {

Lawrence, J GHartl, D LOchman, HengGM 40322/GM/NIGMS NIH HHS/GM 40995/GM/NIGMS NIH HHS/Comparative StudyResearch Support, U.S. Gov{\textquoteright}t, P.H.S.1991/09/01J Mol Evol. 1991 Sep;33(3):241-50.

}, month = {Sep}, pages = {241-50}, abstract = {

Synonymous and nonsynonymous substitution rates at the loci encoding glyceraldehyde-3-phosphate dehydrogenase (gap) and outer membrane protein 3A (ompA) were examined in 12 species of enteric bacteria. By examining homologous sequences in species of varying degrees of relatedness and of known phylogenetic relationships, we analyzed the patterns of synonymous and nonsynonymous substitutions within and among these genes. Although both loci accumulate synonymous substitutions at reduced rates due to codon usage bias, portions of the gap and ompA reading frames show significant deviation in synonymous substitution rates not attributable to local codon bias. A paucity of synonymous substitutions in portions of the ompA gene may reflect selection for a novel mRNA secondary structure. In addition, these studies allow comparisons of homologous protein-coding sequences (gap) in plants, animals, and bacteria, revealing differences in evolutionary constraints on this glycolytic enzyme in these lineages.

}, keywords = {*Biological Evolution, *Genes, Bacterial, Amino Acid Sequence, Animals, Bacteria/*genetics, Bacterial Outer Membrane Proteins/genetics, Bacterial Proteins/genetics, Base Sequence, Enterobacteriaceae/genetics, Glyceraldehyde-3-Phosphate Dehydrogenases/genetics, Mammals/genetics, Molecular Sequence Data, Mutation, Plants/genetics, Sequence Homology, Nucleic Acid, Species Specificity}, isbn = {0022-2844 (Print)0022-2844 (Linking)}, author = {Lawrence, J. G. and Hartl, D. L. and Ochman, H.} } @article {539821, title = {Optimized strategies for sequence-tagged-site selection in genome mapping}, journal = {Proc Natl Acad Sci U S A}, volume = {88}, number = {18}, year = {1991}, note = {

Palazzolo, M JSawyer, S AMartin, C HSmoller, D AHartl, D LengGM44889/GM/NIGMS NIH HHS/HG00357/HG/NHGRI NIH HHS/Research Support, Non-U.S. Gov{\textquoteright}tResearch Support, U.S. Gov{\textquoteright}t, Non-P.H.S.Research Support, U.S. Gov{\textquoteright}t, P.H.S.1991/09/15Proc Natl Acad Sci U S A. 1991 Sep 15;88(18):8034-8.

}, month = {Sep 15}, pages = {8034-8}, abstract = {

The physical mapping of complex genomes is based on the construction of a genomic library and the determination of the overlaps between the inserts of the mapping clones in order to generate an ordered, cloned representation of nearly all the sequences present in the target genome. Evaluation of the relative efficiency of experimental procedures used to accomplish this goal must minimally include a comparison of the fraction of the genome covered by the ordered arrays (or "contigs"), the average size of the contigs, and the cost, in terms of time and resources, required to generate the map. Sequence-tagged-site (STS) content mapping is one strategy that has been proposed and is being utilized for this type of experiment. This paper describes three STS selection schemes and presents computer simulations of contig-building experiments based on these procedures. The results of these simulations suggest that a nonrandom STS strategy that uses paired probes requires one-third to one-fourth as many STS assays as are required in random and nonpaired approaches, and also results in a map that has both greater genome coverage and a larger average contig size. This strategy promises to reduce the time and cost required to build a high-quality physical map.

}, keywords = {*Sequence Tagged Sites, Base Sequence, Chromosome Mapping/*methods, Cloning, Molecular, Computer Simulation, Genetic Linkage, Genetic Vectors, Genomic Library, Polymerase Chain Reaction}, isbn = {0027-8424 (Print)0027-8424 (Linking)}, author = {Palazzolo, M. J. and Sawyer, S. A. and Martin, C. H. and Smoller, D. A. and Hartl, D. L.} } @article {539571, title = {Population genetics in forensic DNA typing}, journal = {Science}, volume = {254}, number = {5039}, year = {1991}, note = {

Lewontin, R CHartl, D LengReviewNew York, N.Y.1991/12/20Science. 1991 Dec 20;254(5039):1745-50.

}, month = {Dec 20}, pages = {1745-50}, abstract = {

Variable number of tandem repeat (VNTR) sequences are used to link defendants with crimes by matching DNA patterns. The probative value of a match is often calculated by multiplying together the estimated frequencies with which each particular VNTR pattern occurs in a reference database. However, this method is liable to potentially serious errors because ethnic subgroups within major racial categories exhibit genetic differences that are maintained by endogamy. The multiplication procedure currently in use can be made scientifically valid only by extensive sampling of VNTR frequency distributions in a variety of ethnic groups, similar to the ethnic studies of various blood groups done in the past. Alternative approaches for dealing with subpopulation heterogeneity are discussed.

}, keywords = {*DNA Fingerprinting, *Genetics, Medical, *Genetics, Population, Alleles, Blood Group Antigens/genetics, DNA Probes, Ethnic Groups/genetics, European Continental Ancestry Group/genetics, Gene Frequency, Humans, Repetitive Sequences, Nucleic Acid, United States}, isbn = {0036-8075 (Print)0036-8075 (Linking)}, author = {Lewontin, R. C. and Hartl, D. L.} } @article {539451, title = {Rapid determination of nucleotide content and its application to the study of genome structure}, journal = {Nucleic Acids Res}, volume = {19}, number = {19}, year = {1991}, note = {

Krane, D EHartl, D LOchman, HengResearch Support, Non-U.S. Gov{\textquoteright}tResearch Support, U.S. Gov{\textquoteright}t, Non-P.H.S.Research Support, U.S. Gov{\textquoteright}t, P.H.S.ENGLAND1991/10/11Nucleic Acids Res. 1991 Oct 11;19(19):5181-5.

}, month = {Oct 11}, pages = {5181-5}, abstract = {

We have developed a sensitive, reliable and accurate procedure for estimating the base composition of small samples of DNAs. This method has been applied to the analysis of genomic DNAs from several sources including large regions of human DNA cloned as yeast artificial chromosomes. To determine whether the human genome is compartmentalized into large segments of homogeneous base composition, we examined the GC content of a 1.2 megabase contig spanning the cystic fibrosis gene.

}, keywords = {*Base Composition, *Genome, Bacteria/genetics, Bacteriophage lambda/genetics, Chromatography, Thin Layer, Cystic Fibrosis/genetics, Deoxyribonucleotides/*analysis, DNA/chemistry, Genetic Variation/genetics, Genome, Human, Humans, Hypoxanthine Phosphoribosyltransferase/genetics, Yeasts/genetics}, isbn = {0305-1048 (Print)0305-1048 (Linking)}, author = {Krane, D. E. and Hartl, D. L. and Ochman, H.} } @article {539716, title = {Toward cloning and mapping the genome of Drosophila}, journal = {Science}, volume = {254}, number = {5029}, year = {1991}, note = {

Merriam, JAshburner, MHartl, D LKafatos, F CengResearch Support, Non-U.S. Gov{\textquoteright}tResearch Support, U.S. Gov{\textquoteright}t, P.H.S.ReviewNew York, N.Y.1991/10/11Science. 1991 Oct 11;254(5029):221-5.

}, month = {Oct 11}, pages = {221-5}, abstract = {

An ultimate goal of Drosophila genetics is to identify and define the functions of all the genes in the organism. Traditional approaches based on the isolation of mutant genes have been extraordinary fruitful. Recent advances in the manipulation and analysis of large DNA fragments have made it possible to develop detailed molecular maps of the Drosophila genome as the initial steps in determining the complete DNA sequence.

}, keywords = {*Chromosome Mapping, *Cloning, Molecular, *Genome, Animals, Base Sequence, Biological Evolution, Chromosomes, Drosophila melanogaster/*genetics, Gene Rearrangement, Genes, Mutation}, isbn = {0036-8075 (Print)0036-8075 (Linking)}, author = {Merriam, J. and Ashburner, M. and Hartl, D. L. and Kafatos, F. C.} } @article {539501, title = {Unusual codon bias occurring within insertion sequences in Escherichia coli}, journal = {Genetica}, volume = {84}, number = {1}, year = {1991}, note = {

Lawrence, J GHartl, D LengGM 40322/GM/NIGMS NIH HHS/Research Support, U.S. Gov{\textquoteright}t, P.H.S.NETHERLANDS1991/01/01Genetica. 1991;84(1):23-9.

}, pages = {23-9}, abstract = {

The large open reading frames of insertion sequences from Escherichia coli were examined for their spatial pattern of codon usage bias and distribution of rarely used codons. There is a bias in codon usage that is generally lower toward the terminal ends of the coding regions, which is reflected in the occurrence of an excess of nonpreferred codons in the 3{\textquoteright} portions of the coding regions as compared with the 5{\textquoteright} portions. In contrast, typical chromosomal genes have a lower codon usage bias toward the 5{\textquoteright} ends of the coding regions. These results imply that the selective forces reflected in codon usage bias may differ according to position within the coding sequence. In addition, these constraints apparently differ in important ways between genes contained in insertion sequences and those in the chromosome.

}, keywords = {Chromosomes, Bacterial/physiology, Codon/*genetics, DNA Transposable Elements/*genetics, Escherichia coli/*genetics, Open Reading Frames/genetics, Selection, Genetic}, isbn = {0016-6707 (Print)0016-6707 (Linking)}, author = {Lawrence, J. G. and Hartl, D. L.} } @article {538701, title = {Active mariner transposable elements are widespread in natural populations of Drosophila simulans}, journal = {Proc Biol Sci}, volume = {242}, number = {1303}, year = {1990}, note = {

Capy, PChakrani, FLemeunier, FHartl, D LDavid, J RengENGLAND1990/10/22Proc Biol Sci. 1990 Oct 22;242(1303):57-60.

}, month = {Oct 22}, pages = {57-60}, abstract = {

The occurrence of active, or autonomous, mariner elements was investigated by crossing white-peach mutant Drosophila simulans females with wild-type males from various geographic origins. From a total of 194 experimental crosses only 17 failed to produce progeny with eye mosaicism (MOS, i.e. pigmented spots in otherwise white-peach eyes). Therefore, active mariner elements inducing somatic excision of the copy inserted at the white locus are abundant in all populations sampled. In the experimental crosses the frequency of mosaic offspring ranged from 0 to 100\%, showing that the phenotypic expression is highly variable. The MOS phenotype, measured by the number of spots on the eyes, is quite variable within the progeny of single crosses. Although a difference was observed in the average MOS score (percentage of mosaic flies) between northern and southern populations of France, there was no indication of long range variation between geographic populations. Neither was there a systematic difference between recently collected populations and samples kept several years as isofemale lines.

}, keywords = {*DNA Transposable Elements, Animals, Crosses, Genetic, Drosophila/*genetics, Female, Genetics, Population, Male, Mosaicism, Phenotype}, isbn = {0962-8452 (Print)0962-8452 (Linking)}, author = {Capy, P. and Chakrani, F. and Lemeunier, F. and Hartl, D. L. and David, J. R.} } @article {539021, title = {Drosophila nonsense suppressors: functional analysis in Saccharomyces cerevisiae, Drosophila tissue culture cells and Drosophila melanogaster}, journal = {Genetics}, volume = {126}, number = {3}, year = {1990}, note = {

Garza, DMedhora, M MHartl, D Leng1990/11/01Genetics. 1990 Nov;126(3):625-37.

}, month = {Nov}, pages = {625-37}, abstract = {

Amber (UAG) and opal (UGA) nonsense suppressors were constructed by oligonucleotide site-directed mutagenesis of two Drosophila melanogaster leucine-tRNA genes and tested in yeast, Drosophila tissue culture cells and transformed flies. Suppression of a variety of amber and opal alleles occurs in yeast. In Drosophila tissue culture cells, the mutant tRNAs suppress hsp70:Adh (alcohol dehydrogenase) amber and opal alleles as well as an hsp70:beta-gal (beta-galactosidase) amber allele. The mutant tRNAs were also introduced into the Drosophila genome by P element-mediated transformation. No measurable suppression was seen in histochemical assays for Adhn4 (amber), AdhnB (opal), or an amber allele of beta-galactosidase. Low levels of suppression (approximately 0.1-0.5\% of wild type) were detected using an hsp70:cat (chloramphenicol acetyltransferase) amber mutation. Dominant male sterility was consistently associated with the presence of the amber suppressors.

}, keywords = {*Suppression, Genetic, Alcohol Dehydrogenase/antagonists \& inhibitors/genetics, Animals, Base Sequence, Blotting, Western, Cells, Cultured, DNA Transposable Elements, Drosophila melanogaster/*genetics, Molecular Sequence Data, Mutation, Reproduction/genetics, RNA, Transfer, Leu/genetics, Saccharomyces cerevisiae/*genetics, Transformation, Genetic}, isbn = {0016-6731 (Print)0016-6731 (Linking)}, author = {Garza, D. and Medhora, M. M. and Hartl, D. L.} } @article {539806, title = {Inverse polymerase chain reaction}, journal = {Biotechnology (N Y)}, volume = {8}, number = {8}, year = {1990}, note = {

Ochman, HAjioka, J WGarza, DHartl, D LengNature Publishing Company1990/08/01Biotechnology (N Y). 1990 Aug;8(8):759-60.

}, month = {Aug}, pages = {759-60}, keywords = {DNA/analysis, Gene Amplification, Polymerase Chain Reaction/*methods}, isbn = {0733-222X (Print)0733-222X (Linking)}, author = {Ochman, H. and Ajioka, J. W. and Garza, D. and Hartl, D. L.} } @article {538926, title = {The molecular evolution of bacterial alkaline phosphatase: correlating variation among enteric bacteria to experimental manipulations of the protein}, journal = {Mol Biol Evol}, volume = {7}, number = {6}, year = {1990}, note = {

DuBose, R FHartl, D LengGM 08036/GM/NIGMS NIH HHS/GM 30201/GM/NIGMS NIH HHS/Research Support, U.S. Gov{\textquoteright}t, P.H.S.1990/11/01Mol Biol Evol. 1990 Nov;7(6):547-77.

}, month = {Nov}, pages = {547-77}, abstract = {

The phylogenetic distribution of the gene coding for bacterial alkaline phosphatase (phoA) was examined in nine species of enteric bacteria closely related to Escherichia coli. The nucleotide and protein sequences from the E. fergusonii and Serratia marcescens genes are presented. The spatial distribution of replaced amino acid residues in the aligned sequences is shown to be highly nonrandom and can be correlated with specific regions within the tertiary structure of the protein. There is an avoidance of replacements within the beta sheet of the protein, and there is an excess of replacements elsewhere, particularly in solvent-exposed residues. In addition, all positions across alpha helices do not accept replacements with equal frequency; there is a bias toward acceptance of replacements in the carboxyl ends of helices. To examine this further, mutations within the E. coli phoA gene were created using site-directed mutagenesis. The patterns seen from the sequence comparisons were verified in the laboratory-created mutants. The average activity of mutations within or near the beta sheet was approximately one-third of that within or near alpha helices, and multiple mutations within the carboxyl ends of alpha helices always possessed greater activity than did multiple mutations within the corresponding amino ends. The results indicate that identifiable regions within the protein are under different selective pressures and are therefore evolving at different rates.

}, keywords = {*Biological Evolution, *Genetic Variation, Alkaline Phosphatase/*genetics/metabolism, Amino Acid Sequence, Bacteria/genetics, Base Composition, Base Sequence, Blotting, Southern, Escherichia coli/*genetics, Escherichia/*genetics, Genes, Bacterial, Molecular Sequence Data, Mutagenesis, Site-Directed, Phylogeny, Sequence Homology, Nucleic Acid, Serratia marcescens/*genetics, Species Specificity}, isbn = {0737-4038 (Print)0737-4038 (Linking)}, author = {DuBose, R. F. and Hartl, D. L.} } @article {538931, title = {Rapid purification of PCR products for DNA sequencing using Sepharose CL-6B spin columns}, journal = {Biotechniques}, volume = {8}, number = {3}, year = {1990}, note = {

DuBose, R FHartl, D LengGM30201/GM/NIGMS NIH HHS/GM40322/GM/NIGMS NIH HHS/Research Support, U.S. Gov{\textquoteright}t, P.H.S.1990/03/01Biotechniques. 1990 Mar;8(3):271-4.

}, month = {Mar}, pages = {271-4}, keywords = {*Nucleic Acid Amplification Techniques, Base Sequence, Centrifugation, Chromatography, Gel, DNA/*isolation \& purification, Polymerase Chain Reaction/*methods, Sepharose/analogs \& derivatives}, isbn = {0736-6205 (Print)0736-6205 (Linking)}, author = {DuBose, R. F. and Hartl, D. L.} } @article {539156, title = {Evolving theories of enzyme evolution}, journal = {Genetics}, volume = {122}, number = {1}, year = {1989}, note = {

Hartl, D LengGM30201/GM/NIGMS NIH HHS/M40322/PHS HHS/Research Support, U.S. Gov{\textquoteright}t, P.H.S.1989/05/01Genetics. 1989 May;122(1):1-6.

}, month = {May}, pages = {1-6}, keywords = {*Biological Evolution, beta-Galactosidase/genetics, Enzymes/*genetics, Escherichia coli/genetics, Mutation, Polymorphism, Genetic, Substrate Specificity}, isbn = {0016-6731 (Print)0016-6731 (Linking)}, author = {Hartl, D. L.} } @article {538921, title = {An experimental approach to testing modular evolution: directed replacement of alpha-helices in a bacterial protein}, journal = {Proc Natl Acad Sci U S A}, volume = {86}, number = {24}, year = {1989}, note = {

DuBose, R FHartl, D LengGM 08036/GM/NIGMS NIH HHS/GM 30201/GM/NIGMS NIH HHS/Research Support, U.S. Gov{\textquoteright}t, P.H.S.1989/12/01Proc Natl Acad Sci U S A. 1989 Dec;86(24):9966-70.

}, month = {Dec}, pages = {9966-70}, abstract = {

We have used oligonucleotide site-directed mutagenesis to ask whether certain structural motifs in proteins are determined mainly by local interactions among amino acids. Multiple consecutive amino acids in three alpha-helices in the alkaline phosphatase (EC 3.1.3.1) of Escherichia coli have been replaced with helical sequences from four other sources. Altogether, 12 distinct helical replacements were created, 9 of which retain enzymatic activity. Most short stretches of helical sequence can be replaced with unrelated helical sequences without eliminating enzyme activity. Replacements of the carboxyl half of an alpha-helix are less harmful than those of the amino half, and the two together are synergistic rather than additive. These results are consistent with the hypothesis that proteins originally evolved by the assembly of small functional folding units.

}, keywords = {*Biological Evolution, *Protein Conformation, Alkaline Phosphatase/*genetics/metabolism, Amino Acid Sequence, Bacterial Proteins/*genetics/ultrastructure, Escherichia coli/enzymology/*genetics, Kinetics, Molecular Sequence Data, Mutation}, isbn = {0027-8424 (Print)0027-8424 (Linking)}, author = {DuBose, R. F. and Hartl, D. L.} } @article {539061, title = {IS103, a new insertion element in Escherichia coli: characterization and distribution in natural populations}, journal = {Genetics}, volume = {121}, number = {3}, year = {1989}, note = {

Hall, B GParker, L LBetts, P WDuBose, R FSawyer, S AHartl, D LengGM37110/GM/NIGMS NIH HHS/GM40322/GM/NIGMS NIH HHS/Research Support, U.S. Gov{\textquoteright}t, P.H.S.1989/03/01Genetics. 1989 Mar;121(3):423-31.

}, month = {Mar}, pages = {423-31}, abstract = {

IS103 is a previously unknown insertion sequence found in Escherichia coli K12. We have sequenced IS103 and find that it is a 1441-bp element that consists of a 1395-bp core flanked by imperfect 23-bp inverted repeats. IS103 causes a 6-bp duplication of the target sequence into which it inserts. There is a single copy of IS103 present in wild-type E. coli K12 strain HfrC. In strain X342 and its descendents there are two additional copies, one of which is located within the bglF gene. IS103 is capable of excising from within bglF and restoring function of that gene. IS103 exhibits 44\% sequence identity with IS3, suggesting that the two insertion sequences are probably derived from a common ancestor. We have examined the distribution of IS103 in the chromosomes and plasmids of the ECOR collection of natural isolates of E. coli. IS103 is found in 36 of the 71 strains examined, and it strongly tends to inhabit plasmids rather than chromosomes. Comparison of the observed distribution of IS103 with distributions predicted by nine different models for the regulation of transposition according to copy number and of the effects of copy number on fitness suggest that transposition of IS103 is strongly regulated and that it has only minor effects on fitness. The strong clustering of IS103 within one phylogenetic subgroup of the E. coli population despite its presence on plasmids suggests that plasmids tend to remain within closely related strains and that transfer to distantly related strains is inhibited.

}, keywords = {*DNA Transposable Elements, Base Sequence, Cloning, Molecular, Culture Media, DNA/isolation \& purification, Escherichia coli/*genetics, Molecular Sequence Data, Operon, Plasmids, Terminology as Topic}, isbn = {0016-6731 (Print)0016-6731 (Linking)}, author = {Hall, B. G. and Parker, L. L. and Betts, P. W. and DuBose, R. F. and Sawyer, S. A. and Hartl, D. L.} } @article {539011, title = {Mapping the Drosophila genome with yeast artificial chromosomes}, journal = {Science}, volume = {246}, number = {4930}, year = {1989}, note = {

Garza, DAjioka, J WBurke, D THartl, D LengNew York, N.Y.1989/11/03Science. 1989 Nov 3;246(4930):641-6.

}, month = {Nov 3}, pages = {641-6}, abstract = {

The ability to clone large fragments of DNA in yeast artificial chromosomes (YAC{\textquoteright}s) has created the possibility of obtaining global physical maps of complex genomes. For this application to be feasible, most sequences in complex genomes must be able to be cloned in YAC{\textquoteright}s, and most clones must be genetically stable and colinear with the genomic sequences from which they originated (that is, not liable to undergo rearrangement). These requirements have been met with a YAC library containing DNA fragments from Drosophila melanogaster ranging in size up to several hundred kilobase pairs. Preliminary characterization of the Drosophila YAC library was carried out by in situ hybridization of random clones and analysis of clones containing known sequences. The results suggest that most euchromatic sequences can be cloned. The library also contains clones in which the inserted DNA is derived from the centromeric heterochromatin. The locations of 58 clones collectively representing about 8 percent of the euchromatic genome are presented.

}, keywords = {*Chromosome Mapping, *Genes, Animals, Chromosomes, Fungal, Cloning, Molecular, Drosophila melanogaster/*genetics, Genomic Library, Heterochromatin/analysis, Recombination, Genetic, Saccharomyces cerevisiae/genetics, Salivary Glands/cytology}, isbn = {0036-8075 (Print)0036-8075 (Linking)}, author = {Garza, D. and Ajioka, J. W. and Burke, D. T. and Hartl, D. L.} } @article {539496, title = {Phylogenetic analysis using insertion sequence fingerprinting in Escherichia coli}, journal = {Mol Biol Evol}, volume = {6}, number = {1}, year = {1989}, note = {

Lawrence, J GDykhuizen, D EDuBose, R FHartl, D LengGM 30201/GM/NIGMS NIH HHS/Comparative StudyResearch Support, U.S. Gov{\textquoteright}t, P.H.S.1989/01/01Mol Biol Evol. 1989 Jan;6(1):1-14.

}, month = {Jan}, pages = {1-14}, abstract = {

Chromosomal DNA from 23 closely related, pathogenic strains of Escherichia coli was digested and probed for the insertion sequences IS1, IS2, IS4, IS5, and IS30. Under the assumption that elements residing in DNA restriction fragments of the same apparent length are identical by descent, parsimony analysis of these characters yielded a unique phylogenetic tree. This analysis not only distinguished among bacterial strains that were otherwise identical in their biochemical characteristics and enzyme electrophoretic mobilities, but certain aspects of the topology of the tree were consistent across several unrelated insertion elements. The distribution of IS elements was then reexamined in light of the inferred phylogenetic relationships to investigate the biological properties of the elements, such as rates of insertion and deletion, and to discover apparent recombinational events. The analysis shows that the pattern of distribution of insertion elements in the bacterial genome is sufficiently stable for epidemiological studies. Although the rate of recombination by conjugation has been postulated to be low, at least two such events appear to have taken place.

}, keywords = {*DNA Transposable Elements, Blotting, Southern, DNA, Bacterial/*genetics, Escherichia coli/*genetics, Phylogeny, Polymorphism, Restriction Fragment Length}, isbn = {0737-4038 (Print)0737-4038 (Linking)}, author = {Lawrence, J. G. and Dykhuizen, D. E. and DuBose, R. F. and Hartl, D. L.} } @article {539161, title = {The physiology of weak selection}, journal = {Genome}, volume = {31}, number = {1}, year = {1989}, note = {

Hartl, D LengGM30201/GM/NIGMS NIH HHS/BiographyHistorical ArticleResearch Support, U.S. Gov{\textquoteright}t, P.H.S.CANADA1989/01/01Genome. 1989;31(1):183-9.

}, pages = {183-9}, abstract = {

Reaction rates in metabolic pathways typically exhibit a kind of diminishing returns in which small variations in the activities of the individual enzymes have very little effect on overall flux. These effects are measured by the control coefficients of the enzymes, and most systems are governed by the summation theorem stating that all control coefficients must sum to unity. One implication is that complex systems will not usually contain single rate limiting steps, but rather be controlled to a greater or lesser extent by many enzymes, each exerting relatively small control. Wright understood this principle in 1934 and used it for his physiological theory of dominance. With respect to small variations in enzyme activity, the principle implies that many small variations should have only mild effects on fitness. Analysis of nucleotide polymorphisms in the genes for glucose-6-phosphate dehydrogenase and alkaline phosphatase in Escherichia coli implies that most amino acid replacements are harmful, and that the average selection coefficient against amino acid replacements that are polymorphic in natural populations is 1 x 10(-7) to 5 x 10(-7). In experiments to determine the a priori distribution of selection coefficients among random amino acid replacements, 25 replacements in beta-galactosidase were created by genetic means, and 22 of these produced selective effects too small to be detected in chemostat competition experiments (s less than 0.004 per generation).

}, keywords = {*Biological Evolution, *Selection, Genetic, Amino Acids/genetics, Animals, Escherichia coli/genetics, Galactosidases/genetics, Genes, Dominant, History, 20th Century, Models, Genetic, Mutation, Polymorphism, Genetic}, isbn = {0831-2796 (Print)0831-2796 (Linking)}, author = {Hartl, D. L.} } @article {540041, title = {Comparative evolution: latent potentials for anagenetic advance}, journal = {Proc Natl Acad Sci U S A}, volume = {85}, number = {14}, year = {1988}, note = {

Stebbins, G LHartl, D LengComparative StudyReview1988/07/01Proc Natl Acad Sci U S A. 1988 Jul;85(14):5141-5.

}, month = {Jul}, pages = {5141-5}, abstract = {

One of the principles that has emerged from experimental evolutionary studies of microorganisms is that polymorphic alleles or new mutations can sometimes possess a latent potential to respond to selection in different environments, although the alleles may be functionally equivalent or disfavored under typical conditions. We suggest that such responses to selection in microorganisms serve as experimental models of evolutionary advances that occur over much longer periods of time in higher organisms. We propose as a general evolutionary principle that anagenic advances often come from capitalizing on preexisting latent selection potentials in the presence of novel ecological opportunity.

}, keywords = {*Biological Evolution, Animals, Bacteria/genetics, Ecology, Genetic Variation, Mutation, Selection, Genetic}, isbn = {0027-8424 (Print)0027-8424 (Linking)}, author = {Stebbins, G. L. and Hartl, D. L.} } @article {539696, title = {Excision of the Drosophila transposable element mariner: identification and characterization of the Mos factor}, journal = {EMBO J}, volume = {7}, number = {7}, year = {1988}, note = {

Medhora, M MMacPeek, A HHartl, D LengGM33741/GM/NIGMS NIH HHS/Research Support, U.S. Gov{\textquoteright}t, P.H.S.ENGLAND1988/07/01EMBO J. 1988 Jul;7(7):2185-9.

}, month = {Jul}, pages = {2185-9}, abstract = {

Genetic and molecular evidence presented in this paper demonstrate that the Mos factor for inherited mosaicism is a special copy of the transposable element mariner. Mosaicism observed in the presence of the Mos (Mosaic) factor results from a high frequency of excision of the mariner element from an insertion site near the white-eye gene in Drosophila mauritiana. The Mos factor promotes the excision of mariner elements from genomic insertion sites other than the site in wpch, and it also promotes its own loss from the genome. Putative transpositions of Mos to new genomic sites have also been observed. A copy of mariner present at a particular site in a Mos strain has been shown to be missing in derived strains in which the Mos factor has been lost, and in strains with putative transpositions. We propose that this copy of mariner is identical to the Mos factor.

}, keywords = {*DNA Transposable Elements, Animals, Chromosome Deletion, Crosses, Genetic, DNA/genetics, Drosophila/*genetics, Mosaicism, Nucleic Acid Hybridization}, isbn = {0261-4189 (Print)0261-4189 (Linking)}, author = {Medhora, M. M. and MacPeek, A. H. and Hartl, D. L.} } @article {539726, title = {Fitness effects of a deletion mutation increasing transcription of the 6-phosphogluconate dehydrogenase gene in Escherichia coli}, journal = {Mol Biol Evol}, volume = {5}, number = {6}, year = {1988}, note = {

Miller, R DDykhuizen, D EHartl, D LengGM30201/GM/NIGMS NIH HHS/Research Support, U.S. Gov{\textquoteright}t, P.H.S.1988/11/01Mol Biol Evol. 1988 Nov;5(6):691-703.

}, month = {Nov}, pages = {691-703}, abstract = {

Directed evolution in microbial organisms provides an experimental approach to molecular evolution in which selective forces can be controlled and favorable mutations analyzed at the molecular level. Here we present an analysis of a mutation selected in Escherichia coli in response to growth in a chemostat in which the limiting nutrient was gluconate. The selectively favored mutation, designated gnd+ (862), occurred in the gene gnd coding for 6-phosphogluconate dehydrogenase, used in gluconate metabolism. Although the allele is strongly favored in chemostats in which the limiting nutrient is gluconate, the selective effects of gnd+ (862) are highly dependent on growth conditions. In chemostats in which growth is limited by a mixture of gluconate and either ribose, glucose, or succinate, the gnd+ (862) allele is favored, disfavored, or neutral according to the relative concentrations of the substrates. The gnd+ (862) allele results from a deletion of 385 nucleotide pairs in the region 5{\textquoteright} to the promoter of gnd, and one endpoint of the deletion is contiguous with the terminus of an IS5 insertion sequence located near gnd in E. coli K12. The gnd+ (862) allele shows a marked increase in transcription that accounts for most or all of the increased enzyme activity.

}, keywords = {*Gene Expression Regulation, *Genes, Bacterial, *Mutation, Alleles, Amino Acid Sequence, Base Sequence, Cloning, Molecular, DNA, Bacterial, Escherichia coli/enzymology/*genetics, Gluconates/metabolism, Molecular Sequence Data, Phosphogluconate Dehydrogenase/*genetics, Restriction Mapping, RNA, Bacterial/biosynthesis, RNA, Messenger/biosynthesis, Selection, Genetic}, isbn = {0737-4038 (Print)0737-4038 (Linking)}, author = {Miller, R. D. and Dykhuizen, D. E. and Hartl, D. L.} } @article {538891, title = {Fitness effects of amino acid replacements in the beta-galactosidase of Escherichia coli}, journal = {Mol Biol Evol}, volume = {5}, number = {5}, year = {1988}, note = {

Dean, A MDykhuizen, D EHartl, D LengGM30201/GM/NIGMS NIH HHS/Research Support, U.S. Gov{\textquoteright}t, P.H.S.1988/09/01Mol Biol Evol. 1988 Sep;5(5):469-85.

}, month = {Sep}, pages = {469-85}, abstract = {

Two genetic procedures were used to obtain amino acid replacements in the lacZ-encoded beta-galactosidase in Escherichia coli. Amino acid replacements could be obtained without regard to their effects on lactase activity by selecting spontaneous mutations that relieved the strong polarity of six nonsense mutations. When streaked on MacConkey-lactose indicator plates, approximately 75\% of these mutants gave strong red lactose-fermenting colonies, and 25\% gave white nonfermenting colonies. Mutants from 11 other nonsense codons were isolated directly using MacConkey-lactose indicator plates, on which positive color indication requires only 0.5\% of the wildtype lactase activity. Among the total of 17 codons, 25 variant beta-galactosidases were identified using electrophoresis and thermal denaturation studies. The fitness effects of these variant beta-galactosidases were determined using competition experiments conducted with lactose as the sole nutrient limiting the growth rate in chemostat cultures. Three of the replacements were deleterious, one was selectively advantageous, and the selective effects of the remaining 21 were undetectable under conditions in which the smallest detectable selection coefficient was approximately 0.4\%/generation.

}, keywords = {*Amino Acids, *Mutation, Alleles, beta-Galactosidase/*genetics, Electrophoresis, Polyacrylamide Gel, Escherichia coli/enzymology/*genetics/growth \& development, Galactosidases/*genetics, Genes, Bacterial, Genotype, Lactose/metabolism}, isbn = {0737-4038 (Print)0737-4038 (Linking)}, author = {Dean, A. M. and Dykhuizen, D. E. and Hartl, D. L.} } @article {539816, title = {Genetic applications of an inverse polymerase chain reaction}, journal = {Genetics}, volume = {120}, number = {3}, year = {1988}, note = {

Ochman, HGerber, A SHartl, D Leng1988/11/01Genetics. 1988 Nov;120(3):621-3.

}, month = {Nov}, pages = {621-3}, abstract = {

A method is presented for the rapid in vitro amplification of DNA sequences that flank a region of known sequence. The method uses the polymerase chain reaction (PCR), but it has the primers oriented in the reverse direction of the usual orientation. The template for the reverse primers is a restriction fragment that has been ligated upon itself to form a circle. This procedure of inverse PCR (IPCR) has many applications in molecular genetics, for example, the amplification and identification of sequences flanking transposable elements. In this paper we show the feasibility of IPCR by amplifying the sequences that flank an IS1 element in the genome of a natural isolate of Escherichia coli.

}, keywords = {*Nucleic Acid Amplification Techniques, Base Sequence, DNA Transposable Elements, DNA, Circular/genetics, DNA-Directed DNA Polymerase/*genetics, Escherichia coli/*genetics, Molecular Sequence Data, Oligonucleotides/chemical synthesis/genetics}, isbn = {0016-6731 (Print)0016-6731 (Linking)}, author = {Ochman, H. and Gerber, A. S. and Hartl, D. L.} } @article {538916, title = {Genetic exchange among natural isolates of bacteria: recombination within the phoA gene of Escherichia coli}, journal = {Proc Natl Acad Sci U S A}, volume = {85}, number = {18}, year = {1988}, note = {

DuBose, R FDykhuizen, D EHartl, D LengGM 08036/GM/NIGMS NIH HHS/GM 30201/GM/NIGMS NIH HHS/Research Support, U.S. Gov{\textquoteright}t, P.H.S.1988/09/01Proc Natl Acad Sci U S A. 1988 Sep;85(18):7036-40.

}, month = {Sep}, pages = {7036-40}, abstract = {

An 1871-nucleotide region including the phoA gene (the structural gene encoding alkaline phosphatase, EC 3.1.3.1) was cloned and sequenced from eight naturally occurring strains of Escherichia coli. Alignment with the sequence from E. coli K-12 made apparent that there were 87 polymorphic nucleotide sites, of which 42 were informative for phylogenetic analysis. Maximum parsimony analysis revealed six equally parsimonious trees with a consistency index of 0.80. Of the 42 informative sites, 22 were inconsistent with each of the maximum parsimony trees. The spatial distribution of the inconsistent sites was highly nonrandom in a manner implying that intragenic recombination has played a major role in determining the evolutionary history of the nine alleles. The implication is that different segments of the phoA gene have different phylogenetic histories.

}, keywords = {*Genes, *Recombination, Genetic, Alkaline Phosphatase/genetics, Base Sequence, Escherichia coli/enzymology/*genetics, Genes, Bacterial, Molecular Sequence Data, Polymorphism, Genetic}, isbn = {0027-8424 (Print)0027-8424 (Linking)}, author = {DuBose, R. F. and Dykhuizen, D. E. and Hartl, D. L.} } @article {538666, title = {Maternally inherited transposon excision in Drosophila simulans}, journal = {Science}, volume = {240}, number = {4849}, year = {1988}, note = {

Bryan, G JHartl, D LengResearch Support, U.S. Gov{\textquoteright}t, P.H.S.New York, N.Y.1988/04/08Science. 1988 Apr 8;240(4849):215-7.

}, month = {Apr 8}, pages = {215-7}, abstract = {

A mutation in the white gene of Drosophila mauritiana resulting from insertion of the transposable element mariner exhibits genetic instability in germline and somatic cells. The instability is greatly enhanced in the presence of the trans-acting autosomal factor Mos, giving eye-color mosaics with pigmented sectors of tissue on an otherwise peach-colored background. The Mos factor, when introduced into the genome of the sibling species Drosophila simulans, exhibited a dramatic maternal effect on expression of the mosaic phenotype. When D. simulans mosaic females (heterozygous for Mos) were crossed with non-mosaic males, two distinct classes of mosaic offspring occurred, one resulting from a maternal effect in which the non-Mos offspring were nevertheless mosaic. The maternal effect was mediated by a product acting after fertilization, and was expressed to varying extents in different backcross strains.

}, keywords = {*DNA Transposable Elements, Animals, Drosophila/*genetics, Eye, Mosaicism, Pigmentation/genetics}, isbn = {0036-8075 (Print)0036-8075 (Linking)}, author = {Bryan, G. J. and Hartl, D. L.} } @article {539366, title = {Why do unrelated insertion sequences occur together in the genome of Escherichia coli?}, journal = {Genetics}, volume = {118}, number = {3}, year = {1988}, note = {

Hartl, D LSawyer, S AengGM30201/GM/NIGMS NIH HHS/Research Support, U.S. Gov{\textquoteright}t, Non-P.H.S.Research Support, U.S. Gov{\textquoteright}t, P.H.S.1988/03/01Genetics. 1988 Mar;118(3):537-41.

}, month = {Mar}, pages = {537-41}, abstract = {

Natural isolates of Escherichia coli are polymorphic for the presence or absence of insertion sequences. Among the ECOR reference collection of 71 natural isolates studied for the number of copies of the insertion sequences IS1, IS2, IS3, IS4, IS5 and IS30, the number of strains containing no copies of the insertion sequences were 11, 28, 23, 43, 46 and 36, respectively. Significant correlations occur in the ECOR strains in the presence or absence of unrelated insertion sequences in the chromosome and plasmid complements. Strains containing any insertion sequence are more likely to contain additional, unrelated insertion sequences than would be expected by chance. We suggest that the positive correlations result from horizontal transfer mediated by plasmids. A branching-process model for the plasmid-mediated transmission of insertion sequences among hosts yields such a correlation, even in the absence of interactions affecting transposition or fitness. The predictions of the model are quantitatively in agreement with the observed correlations among insertion sequences.

}, keywords = {*DNA Transposable Elements, *Genes, Bacterial, Escherichia coli/*genetics, Mathematics, Models, Genetic, Polymorphism, Genetic}, isbn = {0016-6731 (Print)0016-6731 (Linking)}, author = {Hartl, D. L. and Sawyer, S. A.} } @article {539986, title = {Confidence interval for the number of selectively neutral amino acid polymorphisms}, journal = {Proc Natl Acad Sci U S A}, volume = {84}, number = {17}, year = {1987}, note = {

Sawyer, S ADykhuizen, D EHartl, D LengGM30201/GM/NIGMS NIH HHS/Research Support, U.S. Gov{\textquoteright}t, Non-P.H.S.Research Support, U.S. Gov{\textquoteright}t, P.H.S.1987/09/01Proc Natl Acad Sci U S A. 1987 Sep;84(17):6225-8.

}, month = {Sep}, pages = {6225-8}, abstract = {

A statistical approach to the analysis of DNA sequences has been developed, which provides a confidence interval estimate for the proportion of naturally occurring amino acid polymorphisms that are selectively neutral. When applied to the gnd gene coding for 6-phosphogluconate dehydrogenase in a sample of seven natural isolates of Escherichia coli, the method indicates that the proportion of observed amino acid polymorphisms that are selectively neutral is unlikely to be greater than 49\% (upper 95\% confidence limit). On the other hand, the observations are also consistent with a model in which all of the observed amino acid substitutions are mildly deleterious with an average selection coefficient approximating 1.6 X 10(-7). Various models for the distribution of configurations at silent sites are also investigated.

}, keywords = {*Polymorphism, Genetic, Amino Acids/*genetics, Codon/genetics, DNA, Bacterial/genetics, Escherichia coli/enzymology/genetics, Models, Genetic, Mutation, Phosphogluconate Dehydrogenase/genetics, Selection, Genetic}, isbn = {0027-8424 (Print)0027-8424 (Linking)}, author = {Sawyer, S. A. and Dykhuizen, D. E. and Hartl, D. L.} } @article {539981, title = {Distribution and abundance of insertion sequences among natural isolates of Escherichia coli}, journal = {Genetics}, volume = {115}, number = {1}, year = {1987}, note = {

Sawyer, S ADykhuizen, D EDuBose, R FGreen, LMutangadura-Mhlanga, TWolczyk, D FHartl, D LengGM08036/GM/NIGMS NIH HHS/GM30201/GM/NIGMS NIH HHS/Research Support, U.S. Gov{\textquoteright}t, Non-P.H.S.Research Support, U.S. Gov{\textquoteright}t, P.H.S.1987/01/01Genetics. 1987 Jan;115(1):51-63.

}, month = {Jan}, pages = {51-63}, abstract = {

A reference collection of 71 natural isolates of Escherichia coli (the ECOR collection) has been studied with respect to the distribution and abundance of transposable insertion sequences using DNA hybridization. The data include 1173 occurrences of six unrelated insertion sequences (IS1, IS2, IS3, IS4, IS5 and IS30). The number of insertion elements per strain, and the sizes of DNA restriction fragments containing them, is highly variable and can be used to discriminate even among closely related strains. The occurrence and abundance of pairs of unrelated insertion sequences are apparently statistically independent, but significant correlations result from stratifications in the reference collection. However, there is a highly significant positive association among the insertion sequences considered in the aggregate. Nine branching process models, which differ in assumptions regarding the regulation of transposition and the effect of copy number on fitness, have been evaluated with regard to their fit of the observed distributions. No single model fits all copy number distributions. The best models incorporate no regulation of transposition and a moderate to strong decrease in fitness with increasing copy number for IS1 and IS5, strong regulation of transposition and a negligible to weak decrease in fitness with increasing copy number for IS3, and less than strong regulation of transposition for IS2, IS4 and IS30.

}, keywords = {*DNA Transposable Elements, Base Sequence, Chromosomes, Bacterial, DNA, Bacterial/genetics, Escherichia coli/*genetics/isolation \& purification, Genetic Variation, Models, Genetic, Multigene Family, Plasmids}, isbn = {0016-6731 (Print)0016-6731 (Linking)}, author = {Sawyer, S. A. and Dykhuizen, D. E. and DuBose, R. F. and Green, L. and Mutangadura-Mhlanga, T. and Wolczyk, D. F. and Hartl, D. L.} } @article {538671, title = {Heritable somatic excision of a Drosophila transposon}, journal = {Science}, volume = {235}, number = {4796}, year = {1987}, note = {

Bryan, G JJacobson, J WHartl, D LengGM33741/GM/NIGMS NIH HHS/Research Support, U.S. Gov{\textquoteright}t, Non-P.H.S.Research Support, U.S. Gov{\textquoteright}t, P.H.S.New York, N.Y.1987/03/27Science. 1987 Mar 27;235(4796):1636-8.

}, month = {Mar 27}, pages = {1636-8}, abstract = {

A mutation in the white gene of Drosophila mauritiana that results from insertion of the transposable element mariner is genetically unstable in both germ cells and somatic cells. Somatic instability is indicated by the occurrence of animals having mosaic eyes with patches of pigmented cells on a peach-colored background. Normally uncommon, the frequency of mosaicism is so greatly enhanced in a particular mutant strain that virtually every animal in the strain is an eye-color mosaic. The molecular basis of the mosaicism is the excision of the mariner element from its location in the DNA of the white gene in somatic cells. The phenomenon results from a single dominant genetic factor located in chromosome 3. Genetic control over the excision of transposable elements may play a role in determining the persistence of transposable elements in the genome.

}, keywords = {*DNA Transposable Elements, Alleles, Animals, DNA Restriction Enzymes/metabolism, DNA/analysis, Drosophila/*genetics, Homozygote, Mosaicism, Phenotype}, isbn = {0036-8075 (Print)0036-8075 (Linking)}, author = {Bryan, G. J. and Jacobson, J. W. and Hartl, D. L.} } @article {538951, title = {Metabolic flux and fitness}, journal = {Genetics}, volume = {115}, number = {1}, year = {1987}, note = {

Dykhuizen, D EDean, A MHartl, D LengGM 30201/GM/NIGMS NIH HHS/Research Support, U.S. Gov{\textquoteright}t, P.H.S.1987/01/01Genetics. 1987 Jan;115(1):25-31.

}, month = {Jan}, pages = {25-31}, abstract = {

Studies of Escherichia coli under competition for lactose in chemostat cultures have been used to determine the selective effects of variation in the level of the beta-galactoside permease and the beta-galactosidase enzyme. The results determine the adaptive topography of these gene products relative to growth in limiting lactose and enable predictions concerning the selective effects of genetic variants found in natural populations. In the terms of metabolic control theory, the beta-galactosidase enzyme at wild-type-induced levels has a small control coefficient with respect to fitness (C = 0.018), and hence genetic variants resulting in minor changes in enzyme activity have disproportionately small effects on fitness. However, the apparent control coefficient of the beta-galactoside permease at wild-type-induced levels is large (C = 0.551), and hence even minor changes in activity affect fitness. Therefore, we predict that genetic polymorphisms in the lacZ gene are subject to less effective selection in natural populations than are those in the lacY gene. The beta-galactoside permease is also less efficient than might be expected, and possible forces resulting in selection for an intermediate optimum level of permease activity are considered. The selective forces that maintain the lactose operon in a regulated state in natural populations are also discussed.

}, keywords = {*Bacterial Proteins, *Escherichia coli Proteins, beta-Galactosidase/genetics/metabolism, Escherichia coli/genetics/*metabolism, Genetic Variation, Lac Operon, Membrane Transport Proteins/*genetics/metabolism, Models, Biological, Polymorphism, Genetic, Selection, Genetic}, isbn = {0016-6731 (Print)0016-6731 (Linking)}, author = {Dykhuizen, D. E. and Dean, A. M. and Hartl, D. L.} } @article {539151, title = {The molecular approach to evolution: molecular evolutionary genetics}, journal = {Science}, volume = {237}, number = {4816}, year = {1987}, note = {

Hartl, D LengNew York, N.Y.1987/08/14 00:00Science. 1987 Aug 14;237(4816):782.

}, month = {Aug 14}, pages = {782}, isbn = {0036-8075 (Print)0036-8075 (Linking)}, author = {Hartl, D. L.} } @article {539146, title = {Evolution and tinkering: the molecular genetics of bacterial adaption}, journal = {Prog Clin Biol Res}, volume = {218}, year = {1986}, note = {

Hartl, D LengGM30201/GM/NIGMS NIH HHS/GM33741/GM/NIGMS NIH HHS/Research Support, U.S. Gov{\textquoteright}t, P.H.S.1986/01/01Prog Clin Biol Res. 1986;218:161-75.

}, pages = {161-75}, keywords = {*Adaptation, Biological, *Biological Evolution, Bacteria/*genetics, Enzymes/genetics, Escherichia coli/genetics, Genes, Genes, Bacterial, Mutation, Selection, Genetic}, isbn = {0361-7742 (Print)0361-7742 (Linking)}, author = {Hartl, D. L.} } @article {539336, title = {The evolution of DNA sequences in Escherichia coli}, journal = {Philos Trans R Soc Lond B Biol Sci}, volume = {312}, number = {1154}, year = {1986}, note = {

Hartl, D LMedhora, MGreen, LDykhuizen, D EengGM-30201/GM/NIGMS NIH HHS/Research Support, U.S. Gov{\textquoteright}t, P.H.S.ENGLAND1986/01/29Philos Trans R Soc Lond B Biol Sci. 1986 Jan 29;312(1154):191-204.

}, month = {Jan 29}, pages = {191-204}, abstract = {

It is proposed that certain families of transposable elements originally evolved in plasmids and functioned in forming replicon fusions to aid in the horizontal transmission of non-conjugational plasmids. This hypothesis is supported by the finding that the transposable elements Tn3 and gamma delta are found almost exclusively in plasmids, and also by the distribution of the unrelated insertion sequences IS4 and IS5 among a reference collection of 67 natural isolates of Escherichia coli. Each insertion sequence was found to be present in only about one-third of the strains. Among the ten strains found to contain both insertion sequences, the number of copies of the elements was negatively correlated. With respect to IS5, approximately half of the strains containing a chromosomal copy of the insertion element also contained copies within the plasmid complement of the strain.

}, keywords = {*Biological Evolution, Base Sequence, Chromosomes, Bacterial/analysis, DNA Transposable Elements, DNA, Bacterial/*genetics, Escherichia coli/*genetics, Genetic Variation, Models, Genetic, Plasmids, Recombination, Genetic}, isbn = {0962-8436 (Print)0962-8436 (Linking)}, author = {Hartl, D. L. and Medhora, M. and Green, L. and Dykhuizen, D. E.} } @article {538886, title = {Fitness as a function of beta-galactosidase activity in Escherichia coli}, journal = {Genet Res}, volume = {48}, number = {1}, year = {1986}, note = {

Dean, A MDykhuizen, D EHartl, D LengGM 30201/GM/NIGMS NIH HHS/Research Support, U.S. Gov{\textquoteright}t, P.H.S.ENGLAND1986/08/01Genet Res. 1986 Aug;48(1):1-8.

}, month = {Aug}, pages = {1-8}, keywords = {beta-Galactosidase/genetics/*metabolism, Escherichia coli/enzymology/genetics/*growth \& development, Galactosidases/*metabolism, Mutation, Selection, Genetic}, isbn = {0016-6723 (Linking)}, author = {Dean, A. M. and Dykhuizen, D. E. and Hartl, D. L.} } @article {539231, title = {The molecular biology of natural selection: reply to burton and place}, journal = {Genetics}, volume = {114}, number = {3}, year = {1986}, note = {

Hartl, D LDean, A MDykhuizen, D Eeng1986/11/01 00:00Genetics. 1986 Nov;114(3):1037-9.

}, month = {Nov}, pages = {1037-9}, isbn = {0016-6731 (Print)0016-6731 (Linking)}, author = {Hartl, D. L. and Dean, A. M. and Dykhuizen, D. E.} } @article {539411, title = {Molecular structure of a somatically unstable transposable element in Drosophila}, journal = {Proc Natl Acad Sci U S A}, volume = {83}, number = {22}, year = {1986}, note = {

Jacobson, J WMedhora, M MHartl, D LengGM08036/GM/NIGMS NIH HHS/GM33741/GM/NIGMS NIH HHS/Research Support, U.S. Gov{\textquoteright}t, P.H.S.1986/11/01Proc Natl Acad Sci U S A. 1986 Nov;83(22):8684-8.

}, month = {Nov}, pages = {8684-8}, abstract = {

A transposable element has been isolated from an unstable white mutation in Drosophila mauritiana, a sibling species of Drosophila melanogaster. The unstable white-peach (wpch) allele exhibits a spectrum of germ-line and somatic mutability more similar to insertion mutations in maize and in the nematode Caenorhabditis elegans than has been reported for insertion mutations in Drosophila. The inserted element mariner is 1286 nucleotides long and has terminal inverted repeats. The element contains a single open reading frame encoding 346 amino acids. A duplication of 2 base pairs of white sequence is present at the insertion site. Mariner is present in approximately 20 copies in the D. mauritiana genome, is present from 0 to 7 copies in other members of the sibling species group, and is apparently absent from the genome of D. melanogaster.

}, keywords = {*DNA Transposable Elements, Alleles, Animals, Base Sequence, Chromosome Mapping, Cloning, Molecular, Drosophila/*genetics, Mutation}, isbn = {0027-8424 (Print)0027-8424 (Linking)}, author = {Jacobson, J. W. and Medhora, M. M. and Hartl, D. L.} } @article {539946, title = {Antibiotic resistance and population structure in Escherichia coli from free-ranging African yellow baboons}, journal = {Appl Environ Microbiol}, volume = {50}, number = {4}, year = {1985}, note = {

Routman, EMiller, R DPhillips-Conroy, JHartl, D LengGM30201/GM/NIGMS NIH HHS/Comparative StudyResearch Support, U.S. Gov{\textquoteright}t, Non-P.H.S.Research Support, U.S. Gov{\textquoteright}t, P.H.S.1985/10/01Appl Environ Microbiol. 1985 Oct;50(4):749-54.

}, month = {Oct}, pages = {749-54}, abstract = {

Two collections of Escherichia coli from human hosts and one from free-ranging African yellow baboons were examined for the ability to utilize various sugars (biotype) and for resistance to antibiotics. The frequency of antibiotic resistance in the E. coli flora of baboons that feed regularly in village garbage dumps was found to be no greater than that in baboons not associated with human habitation. The frequency of antibiotic resistance in E. coli isolated from baboons is similar to that in E. coli isolated from humans before the widespread use of antibiotics but significantly lower than that in recent isolates from humans. The biotype data indicate that the amount and distribution of genetic variation in the E. coli among free-ranging baboon troops are similar to those in isolates from humans. However, E. coli isolates from baboons are able to utilize a greater variety of sugars as their sole carbon source, possibly because of a greater variety of sugars in the baboon diet.

}, keywords = {Animals, Animals, Wild, Anti-Bacterial Agents/pharmacology, Carbohydrate Metabolism, Drug Resistance, Microbial, Escherichia coli/drug effects/growth \& development/*isolation \& purification, Humans, Papio/*microbiology, Species Specificity}, isbn = {0099-2240 (Print)0099-2240 (Linking)}, author = {Routman, E. and Miller, R. D. and Phillips-Conroy, J. and Hartl, D. L.} } @article {539406, title = {Coupled instability of two X-linked genes in Drosophila mauritiana: germinal and somatic mutability}, journal = {Genetics}, volume = {111}, number = {1}, year = {1985}, note = {

Jacobson, J WHartl, D LengGM33741/GM/NIGMS NIH HHS/Research Support, U.S. Gov{\textquoteright}t, P.H.S.1985/09/01Genetics. 1985 Sep;111(1):57-65.

}, month = {Sep}, pages = {57-65}, abstract = {

A highly unstable allele has been isolated at the white locus of Drosophila mauritiana, a sibling species of D. melanogaster. This allele, white-peach (wpch), mutates spontaneously in males and females to give both wild-type and bleached-white derivatives. The mutation frequency is about 10(-3) mutations/generation. There is no evidence for clustering among mutant progeny, and phenotypically wpch flies with mosaic patches of wild-type tissue in the eyes are frequently recovered. Another X-linked locus, plum, is destabilized when wpch is on the same X chromosome.

}, keywords = {*Genetic Linkage, *Mutation, *X Chromosome, Alleles, Animals, Crosses, Genetic, Drosophila melanogaster/genetics, Drosophila/*genetics, Female, Genetic Complementation Test, Male, Phenotype}, isbn = {0016-6731 (Print)0016-6731 (Linking)}, author = {Jacobson, J. W. and Hartl, D. L.} } @article {538966, title = {Joint distribution of insertion elements IS4 and IS5 in natural isolates of Escherichia coli}, journal = {Genetics}, volume = {111}, number = {2}, year = {1985}, note = {

Dykhuizen, D ESawyer, S AGreen, LMiller, R DHartl, D LengGM 30201/GM/NIGMS NIH HHS/Research Support, U.S. Gov{\textquoteright}t, P.H.S.1985/10/01Genetics. 1985 Oct;111(2):219-31.

}, month = {Oct}, pages = {219-31}, abstract = {

A reference collection of natural isolates of Escherichia coli has been studied in order to determine the distribution, abundance and joint occurrence of DNA insertion elements IS4 and IS5. Among these isolates, 36\% were found to contain IS4 and 30\% were found to contain IS5. Among strains containing IS4 the mean number of copies per strain was 4.4 +/- 0.8; the comparable figure for IS5 was 3.7 +/- 1.0. Although the presence of the elements among the isolates was independent, among those isolates containing both IS4 and IS5, there was a significant negative correlation in the number of copies of the elements. The reference collection was also studied for the presence of the DNA sequences flanking the single copy of IS4 in the chromosome of E. coli K12. Homologous sequences were found in only 26\% of the isolates. The sequences flanking the IS4 invariably occur together, and their presence is significantly correlated with the presence of IS4. In eight of the strains that carry these flanking sequences, an IS4 is located between them, and the sequences are present at the homologous position as in the K12 strain. We suggest that IS4 and its flanking sequences share a common mechanism of dissemination, such as plasmids, and we present evidence that they are included in a much larger transposable element.

}, keywords = {*DNA Transposable Elements, Base Composition, DNA Restriction Enzymes, Escherichia coli/*genetics/isolation \& purification, Nucleic Acid Hybridization, Plasmids, Species Specificity}, isbn = {0016-6731 (Print)0016-6731 (Linking)}, author = {Dykhuizen, D. E. and Sawyer, S. A. and Green, L. and Miller, R. D. and Hartl, D. L.} } @article {539256, title = {Limits of adaptation: the evolution of selective neutrality}, journal = {Genetics}, volume = {111}, number = {3}, year = {1985}, note = {

Hartl, D LDykhuizen, D EDean, A MengGM30201/GM/NIGMS NIH HHS/GM33741/GM/NIGMS NIH HHS/Research Support, U.S. Gov{\textquoteright}t, P.H.S.1985/11/01Genetics. 1985 Nov;111(3):655-74.

}, month = {Nov}, pages = {655-74}, abstract = {

Many enzymes in intermediary metabolism manifest saturation kinetics in which flux is a concave function of enzyme activity and often of the Michaelis-Menten form. The result is that, when natural selection favors increased enzyme activity so as to maximize flux, a point of diminishing returns will be attained in which any increase in flux results in a disproportionately small increase in fitness. Enzyme activity ultimately will reach a level at which the favorable effect of an increase in activity is of the order 1/(4Ne) or smaller, where Ne is the effective population number. At this point, many mutations that result in small changes in activity will result in negligible changes in fitness and will be selectively nearly neutral. We propose that this process is a mechanism whereby conditions for the occurrence of nearly neutral mutations and gene substitutions can be brought about by the long-continued action of natural selection. Evidence for the hypothesis derives from metabolic theory, direct studies of flux, studies of null and other types of alleles in Drosophila melanogaster and chemostat studies in Escherichia coli. Limitations and complications of the theory include changes in environment or genetic background, enzymes with sharply defined optima of activity, overdominance, pleiotropy, multifunctional enzymes and branched metabolic pathways. We conclude that the theory is a useful synthesis that unites many seemingly unrelated observations. The principal theoretical conclusion is that the conditions for the occurrence of neutral evolution can be brought about as an indirect result of the action of natural selection.

}, keywords = {*Adaptation, Physiological, *Biological Evolution, *Models, Genetic, *Selection, Genetic, Alleles, Animals, Drosophila melanogaster/genetics, Enzymes/metabolism, Gene Frequency}, isbn = {0016-6731 (Print)0016-6731 (Linking)}, author = {Hartl, D. L. and Dykhuizen, D. E. and Dean, A. M.} } @article {538571, title = {T-cell receptor beta-chain expression: dependence on relatively few variable region genes}, journal = {Science}, volume = {229}, number = {4713}, year = {1985}, note = {

Behlke, M ASpinella, D GChou, H SSha, WHartl, D LLoh, D YengGM07200/GM/NIGMS NIH HHS/Research Support, Non-U.S. Gov{\textquoteright}tResearch Support, U.S. Gov{\textquoteright}t, P.H.S.New York, N.Y.1985/08/09Science. 1985 Aug 9;229(4713):566-70.

}, month = {Aug 9}, pages = {566-70}, abstract = {

Fifteen independently isolated complementary DNA clones that contain T-cell receptor (TCR) V beta genes were sequenced and found to represent 11 different V beta genes. When compared with known sequences, 14 different V beta genes could be defined from a total of 25 complementary DNA{\textquoteright}s; 11 clones therefore involved repeated usage of previously identified V beta{\textquoteright}s. Based on these data, we calculate a maximum likelihood estimate of the number of expressed germline V beta genes to be 18 with an upper 95 percent confidence bound of 30 genes. Southern blot analysis has shown that most of these genes belong to single element subfamilies which show very limited interstrain polymorphism. The TCR beta-chain diversity appears to be generated from a limited V beta gene pool primarily by extensive variability at the variable-diversity-joining (V-D-J) junctional site, with no evidence for the involvement of somatic hypermutation.

}, keywords = {*Genetic Variation, Alleles, Animals, Base Sequence, Chromosome Mapping, Cloning, Molecular, DNA, Gene Pool, Humans, Hybridomas, Immunoglobulin Variable Region/genetics, Mice, Mice, Inbred BALB C/genetics, Mice, Inbred C57BL/genetics, Mice, Inbred Strains/genetics, Receptors, Antigen, T-Cell/*genetics, Species Specificity, Spleen, T-Lymphocytes, Thymus Gland}, isbn = {0036-8075 (Print)0036-8075 (Linking)}, author = {Behlke, M. A. and Spinella, D. G. and Chou, H. S. and Sha, W. and Hartl, D. L. and Loh, D. Y.} } @article {539251, title = {Accessory DNAs in the bacterial gene pool: playground for coevolution}, journal = {Ciba Found Symp}, volume = {102}, year = {1984}, note = {

Hartl, D LDykhuizen, D EBerg, D EengAI14267/AI/NIAID NIH HHS/AI18980/AI/NIAID NIH HHS/GM24886/GM/NIGMS NIH HHS/Research Support, U.S. Gov{\textquoteright}t, P.H.S.NETHERLANDS1984/01/01Ciba Found Symp. 1984;102:233-45.

}, pages = {233-45}, abstract = {

Chemostat studies of bacteria that harbour the prokaryotic transposable elements Tn5 and Tn10 and the temperate phages lambda, Mu, P1 and P2 have shown that these accessory DNA elements confer a selective advantage on their hosts. We propose that similar selective effects provided the initial impetus for the evolution of nascent accessory DNA elements in primitive bacterial populations. In subsequent evolution the elements acquired or perfected the {\textquoteright}selfish{\textquoteright} characteristics of over-replication and horizontal transmission. Such selfish traits led to the dissemination of accessory DNAs among commensal strains, species and genera, genetically interconnecting them to create a {\textquoteright}commonwealth{\textquoteright} of species that potentially share a common gene pool. The involvement of accessory DNAs in genetic exchange provides selection at the population level for refinement and diversification of the elements and for regulation of their replication, transposition and transfer among cells. The diversity of intracellular environments encountered by the elements imposes constraints on their evolution while at the same time altering the selection pressures operating on conventional chromosomal genes. This process of coevolution of accessory DNAs with the genomes of their diverse hosts has led to a unique population structure and mechanism of genetic exchange among bacteria, which constitutes the most effective adaptive strategy yet devised by selection.

}, keywords = {*Genes, Bacterial, Adaptation, Biological, Bacteriophages, Biological Evolution, DNA Transposable Elements, DNA/*genetics, Plasmids}, isbn = {0300-5208 (Print)0300-5208 (Linking)}, author = {Hartl, D. L. and Dykhuizen, D. E. and Berg, D. E.} } @article {539041, title = {Distribution of DNA insertion element IS5 in natural isolates of Escherichia coli}, journal = {Proc Natl Acad Sci U S A}, volume = {81}, number = {14}, year = {1984}, note = {

Green, LMiller, R DDykhuizen, D EHartl, D LengGM30201/GM/NIGMS NIH HHS/Research Support, U.S. Gov{\textquoteright}t, P.H.S.1984/07/01Proc Natl Acad Sci U S A. 1984 Jul;81(14):4500-4.

}, month = {Jul}, pages = {4500-4}, abstract = {

DNA from Escherichia coli strains in a reference collection of 72 recent natural isolates (ECOR strains) and 25 natural isolates from the "pre-antibiotic" period 1930-1940 (Murray strains) were studied to determine the genomic abundance of insertion element IS5 and the size of genomic restriction fragments carrying sequences homologous to IS5. Among the ECOR strains, nearly two-thirds lack DNA sequences that hybridize with IS5, and one-half of the remainder have only one copy. Among strains in which IS5 is present, extensive variation in the size of IS5-bearing restriction fragments occurs, in many cases allowing distinction among strains that are judged to be nearly identical in genotype because of the identical electrophoretic mobility of the enzyme coded by each of 11 chromosomal loci. Among the Murray strains in which IS5 is present, the average number of elements per strain is larger, but not markedly so, than among recent isolates. Comparison between duplicate strains in the Murray collection suggests that the rate of accumulation of IS5 elements in prolonged storage in stab tubes corresponds to an apparent probability of transposition of approximately 0.008 +/- 0.002 per IS5 element per year. Because of the extensive genetic variation among strains, insertion elements such as IS5 would seem to be convenient genetic markers with which to detect recent common ancestry among strains.

}, keywords = {*DNA Transposable Elements, Animals, Cattle, Deoxyribonuclease EcoRI, Dipodomys, DNA Restriction Enzymes/metabolism, DNA, Bacterial/analysis, DNA/analysis, Dogs, Escherichia coli/*genetics, Female, Genetic Variation, Genotype, Humans, Male, Nucleic Acid Hybridization, Species Specificity}, isbn = {0027-8424 (Print)0027-8424 (Linking)}, author = {Green, L. and Miller, R. D. and Dykhuizen, D. E. and Hartl, D. L.} } @article {540006, title = {Interspecific DNA transformation in Drosophila}, journal = {Proc Natl Acad Sci U S A}, volume = {81}, number = {23}, year = {1984}, note = {

Scavarda, N JHartl, D LengGM33741/GM/NIGMS NIH HHS/Comparative StudyResearch Support, U.S. Gov{\textquoteright}t, P.H.S.1984/12/01Proc Natl Acad Sci U S A. 1984 Dec;81(23):7515-9.

}, month = {Dec}, pages = {7515-9}, abstract = {

A DNA fragment that includes the wild-type rosy (ry+) gene of Drosophila melanogaster has been introduced by microinjection into the germ line of the reproductively isolated species Drosophila simulans and incorporated into the D. simulans genome. Transformation was mediated by the transposable element P, which occurs in the genome of most natural populations of D. melanogaster but not in D. simulans. Rubin and Spradling [Rubin, G.M. \& Spradling, A.C. (1982) Science 218, 348-353] have previously shown that the ry+ DNA fragment, which is flanked by recognition sequences of P element, can transform the germ line of D. melanogaster. Successful transformation in D. simulans indicates that the P element continues to function as a transposable element in the D. simulans genome. Moreover, the ry+ gene of D. melanogaster functions in the genome of D. simulans to produce normal eye color, despite the estimated 1 to 5 million yr of reproductive isolation since the evolutionary divergence of these species. Interspecific DNA transformation provides a useful method for the study of genetic differences affecting gene expression among related but reproductively isolated species.

}, keywords = {*Transformation, Genetic, Animals, DNA Transposable Elements, DNA/isolation \& purification, Drosophila melanogaster/*genetics, Drosophila/*genetics, Genes, Nucleic Acid Hybridization, Species Specificity}, isbn = {0027-8424 (Print)0027-8424 (Linking)}, author = {Scavarda, N. J. and Hartl, D. L.} } @article {539246, title = {The population genetics of Escherichia coli}, journal = {Annu Rev Genet}, volume = {18}, year = {1984}, note = {

Hartl, D LDykhuizen, D Eeng30201/PHS HHS/Research Support, U.S. Gov{\textquoteright}t, P.H.S.Review1984/01/01Annu Rev Genet. 1984;18:31-68.

}, pages = {31-68}, abstract = {

E. coli is a successful and diverse group of organisms, well defined by DNA hybridization within the Enterobacteriacae and including the closely related organisms Shigella and the Alkalescens-Dispar biogroup. The primary habitat of E. coli is the lower intestinal tract of warm-blooded animals, which is colonized shortly after birth. At any one time, most normal individuals carry several strains of E. coli in their intestinal tract, including a small number of resident clones exhibiting a rate of replacement measured in weeks or months and a much larger number of transient clones that are replaced in a matter of days or weeks. The secondary habitats of E. coli are soil, sediment, and water, where its half life is thought to be only a few days. Pathogenic forms of E. coli are associated with diarrheal diseases, urinary tract infections, neonatal meningitis, nosocomial infections, and in infections of domesticated animals. E. coli populations contain much genetic diversity, more than is found in most eukaryotes. Genetic diversity has been studied from the standpoint of (a) serology with respect to surface antigens, (b) biogrouping with respect to variable characters such as nutritional versatility, antibiotic resistance, and bacteriophage susceptibility, (c) electrophoresis of enzymes of intermediary metabolism or outer membrane proteins, (d) DNA hybridization, (e) restriction-fragment length polymorphisms, (f) DNA sequences, (g) insertion sequences, and (h) plasmids. However identified, strains of E. coli appear to have a wide, but not totally indiscriminate, host range. Aside from genes directly associated with virulence, genetic divergence between pathogenic and nonpathogenic strains, although statistically significant, is not pronounced. Electrophoretic studies indicate that, while some serotypes may represent a single genetic clone almost exclusively, other serotypes may represent two or more genetically unrelated clones. Unrelated clones may therefore converge to the same or very similar serotypes. Electrophoresis has also been used to define three groups of clones among natural isolates, perhaps corresponding to subspecies of E. coli. These groups are worldwide in distribution and have a wide host range. E. coli populations exhibit great linkage disequilibrium, which occurs as highly nonrandom combinations of alleles at different loci. Reproduction is evidently largely asexual, with insufficient genetic recombination to dissipate linkage disequilibrium.(ABSTRACT TRUNCATED AT 400 WORDS)

}, keywords = {Animal Diseases/microbiology, Animals, Bacterial Proteins/analysis, Coliphages, DNA Transposable Elements, DNA, Bacterial/analysis, Electrophoresis, Enterobacteriaceae/classification, Escherichia coli Infections/microbiology/veterinary, Escherichia coli/classification/*genetics/pathogenicity, Female, Humans, Intestines/microbiology, Male, Mammals/microbiology, Nucleic Acid Hybridization, Plasmids, Selection, Genetic, Serotyping, Soil Microbiology, Water Microbiology}, isbn = {0066-4197 (Print)0066-4197 (Linking)}, author = {Hartl, D. L. and Dykhuizen, D. E.} } @article {538941, title = {Potential for hitchhiking in the eda-edd-zwf gene cluster of Escherichia coli}, journal = {Genet Res}, volume = {43}, number = {3}, year = {1984}, note = {

Dykhuizen, D Ede Framond, JHartl, D LengGM30201/GM/NIGMS NIH HHS/Research Support, U.S. Gov{\textquoteright}t, P.H.S.ENGLAND1984/06/01Genet Res. 1984 Jun;43(3):229-39.

}, month = {Jun}, pages = {229-39}, keywords = {*Genes, Bacterial, *Genetic Linkage, *Hexuronic Acids, Alleles, Escherichia coli/*genetics, Genetic Variation, Gluconates/metabolism, Glucuronates/metabolism, Selection, Genetic, Uronic Acids/metabolism}, isbn = {0016-6723 (Linking)}, author = {Dykhuizen, D. E. and de Framond, J. and Hartl, D. L.} } @article {538946, title = {Selective neutrality of glucose-6-phosphate dehydrogenase allozymes in Escherichia coli}, journal = {Mol Biol Evol}, volume = {1}, number = {2}, year = {1984}, note = {

Dykhuizen, D Ede Framond, JHartl, D LengGM30201/GM/NIGMS NIH HHS/Research Support, U.S. Gov{\textquoteright}t, P.H.S.1984/02/01Mol Biol Evol. 1984 Feb;1(2):162-70.

}, month = {Feb}, pages = {162-70}, abstract = {

Six naturally occurring alleles representing four electromorphs of the enzyme glucose-6-phosphate dehydrogenase were transferred by P1-mediated transduction from natural isolates of Escherichia coli into the genetic background of E. coli K12 and were studied in pairwise competition in chemostats limited for glucose in order to estimate differences in growth rate associated with the alleles. Although the level of resolution of such experiments is a growth rate differential of approximately 0.002 h-1, no significant differences among the strains were found. Studies of apparent Km and Vmax in crude enzyme extracts of the strains also failed to reveal any significant differences among the electromorphs. These results support the view that the alleles are selectively neutral or nearly neutral under these conditions.

}, keywords = {Alleles, Escherichia coli/enzymology/*genetics, Genes, Bacterial, Genetic Variation, Glucosephosphate Dehydrogenase/*genetics, Selection, Genetic, Transduction, Genetic}, isbn = {0737-4038 (Print)0737-4038 (Linking)}, author = {Dykhuizen, D. E. and de Framond, J. and Hartl, D. L.} } @article {539721, title = {Specific deletion occurring in the directed evolution of 6-phosphogluconate dehydrogenase in Escherichia coli}, journal = {Genetics}, volume = {108}, number = {4}, year = {1984}, note = {

Miller, R DDykhuizen, D EGreen, LHartl, D LengGM30201/GM/NIGMS NIH HHS/Research Support, U.S. Gov{\textquoteright}t, P.H.S.1984/12/01Genetics. 1984 Dec;108(4):765-72.

}, month = {Dec}, pages = {765-72}, abstract = {

A novel genetic change leading to increased activity of 6-phosphogluconate dehydrogenase (6PGD) in E. coli has been observed. The mutation is a deletion of approximately 0.4 kilobase pairs occurring between the structural gene of 6PGD (gnd) and one copy of an insertion element (IS5) found normally in E. coli K12 a few hundred base pairs upstream (counterclockwise) from gnd at 44 minutes on the conventional genetic map. The deletion is associated with a threefold higher activity of 6PGD and a 57\% increase in the maximum growth rate when cells are grown in gluconate.

}, keywords = {Bacterial Proteins/*genetics, Chromosome Deletion, Chromosomes, Bacterial/ultrastructure, Escherichia coli/enzymology/*genetics, Mutation, Phosphogluconate Dehydrogenase/*genetics, Selection, Genetic}, isbn = {0016-6731 (Print)0016-6731 (Linking)}, author = {Miller, R. D. and Dykhuizen, D. E. and Green, L. and Hartl, D. L.} } @article {538591, title = {Evolution of transposons: natural selection for Tn5 in Escherichia coli K12}, journal = {Genetics}, volume = {103}, number = {4}, year = {1983}, note = {

Biel, S WHartl, D LengGM30201/GM/NIGMS NIH HHS/Comparative StudyResearch Support, U.S. Gov{\textquoteright}t, P.H.S.1983/04/01Genetics. 1983 Apr;103(4):581-92.

}, month = {Apr}, pages = {581-92}, abstract = {

A novel in vivo effect of the transposable element Tn5 has been observed in chemostats when certain isogenic Tn5 and non-Tn5 strains of Escherichia coli compete for a limiting carbon source in the absence of kanamycin. The Tn5-bearing strain has a more rapid growth rate and increases in frequency from 50\% to 90\% within the first 15 to 20 generations. The effect occurs when Tn5 is inserted at a variety of chromosomal locations or when the element is carried by an episome, but it is strain specific, having been observed in two out of three strains examined. (For reasons unknown, the effect has not been observed with derivatives of strain CSH12.) Although the growth-rate advantage of Tn5 is independent of nutrient concentration and generation time, it can be reduced by prior adaptation of the strains to limiting conditions, and the amount of reduction is proportional to the length of prior adaptation. The growth-rate effect is evidently not caused by beneficial mutations induced by Tn5 transposition, as Tn5-bearing strains selected in chemostats retain their initial Tn5 position and copy number. However, the effect does not occur in Tn5-112, a transpositionless deletion mutation missing the transposase-coding region of the right-hand IS sequence flanking the element. Since Tn5-112 retains a functional kanamycin-phosphotransferase gene, this gene is not responsible for the growth-rate effect. Thus, the effect evidently requires transposase function, but it does not involve actual transposition of the intact element. Altogether, these data provide a mechanism for the maintenance of Tn5 in bacterial populations in the absence of kanamycin, and they suggest a model for the proliferation and the maintenance of IS sequences and transposable elements in the absence of other identifiable selection pressures.

}, keywords = {*Biological Evolution, *DNA Transposable Elements, Cell Division, Drug Resistance, Microbial, Escherichia coli/*genetics, Genes, Bacterial, Selection, Genetic}, isbn = {0016-6731 (Print)0016-6731 (Linking)}, author = {Biel, S. W. and Hartl, D. L.} } @article {539401, title = {The Experimental Assessment of Fitness in Drosophila. II. a Comparison of Competitive and Noncompetitive Measures}, journal = {Genetics}, volume = {104}, number = {2}, year = {1983}, note = {

Haymer, D SHartl, D Leng1983/06/01 00:00Genetics. 1983 Jun;104(2):343-52.

}, month = {Jun}, pages = {343-52}, abstract = {

Twelve diverse strains of Drosophila melanogaster have been examined with respect to their individual fitness components and with respect to their relative performance under competitive and noncompetitive conditions. Individual fitness components included estimates of time until successful copulation (t), fecundity (f) and egg-to-adult viability (v), and a composite index of overall fitness of the form fv/t was used for comparisons among strains. Noncompetitive performance was assessed in terms of the biomass (standing crop) and productivity of equilibrium experimental populations. Competitive performance was assessed in terms of relative competitive ability vis-a-vis a standard compound-autosome-bearing strain in single-generation tests. A significant correlation was found between the composite index of individual fitness components and the competitive compound-autosome test. Although the biomass and productivity of equilibrium populations were correlated with each other, neither of these noncompetitive measures was correlated with individual fitness components or with the composite index. We suggest that the performance of strains in such noncompetitive tests may be related to what Wright has called the "mean selective value" of the populations. Judging from their association with the composite index of individual fitness components, competitive tests such as the compound-autosome test seem to be related more nearly to the average Darwinian fitness of the populations.

}, isbn = {0016-6731 (Print)0016-6731 (Linking)}, author = {Haymer, D. S. and Hartl, D. L.} } @article {538956, title = {Functional effects of PGI allozymes in Escherichia coli}, journal = {Genetics}, volume = {105}, number = {1}, year = {1983}, note = {

Dykhuizen, D EHartl, D LengGM30201/GM/NIGMS NIH HHS/Comparative StudyResearch Support, U.S. Gov{\textquoteright}t, P.H.S.1983/09/01Genetics. 1983 Sep;105(1):1-18.

}, month = {Sep}, pages = {1-18}, abstract = {

Five alleles representing three electromorphs of phosphoglucose isomerase (PGI) have been transferred from natural isolates of E. coli into the genetic background of E. coli K12 and examined for their effect on growth rate in chemostats limited for glucose or fructose. With glucose limitation, all alleles are selectively neutral or nearly neutral within the limit of resolution of the technique, whether the genetic background is nonmutant or whether it contains a deletion of the locus of glucose-6-phosphate dehydrogenase, the enzyme that provides an alternative metabolic pathway for the substrate of PGI. With fructose limitation, one of the naturally occurring alleles has a small but reproducible detrimental effect on growth rate. A kinetic difference in this detrimental allozyme, apparently relating to an inhibition constant, has been observed in some, but not all, lots of substrate, and a similar difference has also been noted in one of the rare electromorphs that could not be transferred into E. coli K12. These results support a model of genetic variation in which the alleles are neutral or nearly neutral in the prevailing environment but have a potential for selection that can be expressed under the appropriate conditions of environment or genetic background. This hypothesis is discussed in the context of allozyme polymorphisms observed in other organisms.

}, keywords = {Alleles, Escherichia coli/*enzymology/genetics/growth \& development, Fructose/metabolism, Glucose-6-Phosphate Isomerase/genetics/*physiology, Glucose/metabolism, Glucosephosphate Dehydrogenase/genetics, Polymorphism, Genetic, Selection, Genetic}, isbn = {0016-6731 (Print)0016-6731 (Linking)}, author = {Dykhuizen, D. E. and Hartl, D. L.} } @article {539141, title = {Genetics and evolution: evolution of genes and proteins}, journal = {Science}, volume = {221}, number = {4613}, year = {1983}, note = {

Hartl, D LengNew York, N.Y.1983/08/26 00:00Science. 1983 Aug 26;221(4613):847.

}, month = {Aug 26}, pages = {847}, isbn = {0036-8075 (Print)0036-8075 (Linking)}, author = {Hartl, D. L.} } @article {538961, title = {Selection in chemostats}, journal = {Microbiol Rev}, volume = {47}, number = {2}, year = {1983}, note = {

Dykhuizen, D EHartl, D LengGM30201/GM/NIGMS NIH HHS/Research Support, U.S. Gov{\textquoteright}t, P.H.S.Review1983/06/01Microbiol Rev. 1983 Jun;47(2):150-68.

}, month = {Jun}, pages = {150-68}, keywords = {*Selection, Genetic, Bacteria/*growth \& development, Bacteriological Techniques, Bacteriophages/genetics, DNA Transposable Elements, Escherichia coli/genetics/growth \& development, Fungi/*growth \& development, Genetic Engineering, Mutation, Plasmids, Saccharomyces cerevisiae/growth \& development}, isbn = {0146-0749 (Print)0146-0749 (Linking)}, author = {Dykhuizen, D. E. and Hartl, D. L.} } @article {539261, title = {Transposable element IS50 improves growth rate of E. coli cells without transposition}, journal = {Cell}, volume = {35}, number = {2 Pt 1}, year = {1983}, note = {

Hartl, D LDykhuizen, D EMiller, R DGreen, Lde Framond, JengGM30201/GM/NIGMS NIH HHS/Research Support, U.S. Gov{\textquoteright}t, P.H.S.1983/12/01Cell. 1983 Dec;35(2 Pt 1):503-10.

}, month = {Dec}, pages = {503-10}, abstract = {

Insertion sequence IS50R, which encodes the transposase and an inhibitor of transposition of the kanamycin-resistance transposon Tn5, increases the growth rate of E. coli K12 cells relative to that of their otherwise isogenic counterparts during competition in continuous culture. Most clones isolated from chemostats in which selection had occurred retain their original number of copies of IS50R at their original genomic locations, implying that the increased growth rate is not mediated by transposition. The selective advantage due to a single IS50R element averages about 5\% per hour. When the number of copies of IS50R is small, the growth-rate advantage is approximately proportional to the number of copies of IS50R. These results imply that IS50R has effects on cells that are independent of both position and transposition and may be important in the initial selection leading to the appearance of such elements in bacterial populations.

}, keywords = {*DNA Transposable Elements, Chromosomes, Bacterial/physiology, Drug Resistance, Microbial, Escherichia coli/genetics/*growth \& development, Genotype, Kanamycin/toxicity, Nucleic Acid Hybridization}, isbn = {0092-8674 (Print)0092-8674 (Linking)}, author = {Hartl, D. L. and Dykhuizen, D. E. and Miller, R. D. and Green, L. and de Framond, J.} } @article {539226, title = {Allele multiplicity in simple Mendelian disorders}, journal = {Am J Hum Genet}, volume = {34}, number = {6}, year = {1982}, note = {

Hartl, D LCampbell, R BengGM-24886/GM/NIGMS NIH HHS/GM-30351/GM/NIGMS NIH HHS/Research Support, U.S. Gov{\textquoteright}t, Non-P.H.S.Research Support, U.S. Gov{\textquoteright}t, P.H.S.1982/11/01Am J Hum Genet. 1982 Nov;34(6):866-73.

}, month = {Nov}, pages = {866-73}, abstract = {

A model of selection involving two selectively equivalent classes of alleles at a locus is considered. One class consists of normal alleles A1, A2, A3,. . .; the other class consists of detrimental alleles a1, a2, a3, . . . . Mutation within and between allelic classes can occur without restriction, but selection operates in such a way as to maintain an approximately constant overall frequency of A-type and a-type alleles is derived, and it is shown that the distribution of allele frequencies in a sample of detrimental alleles depends on the forward (A to a) mutation rate but not on the selection coefficient, degree of dominance, or mutation rate among a-type alleles. Recurrent mutation therefore generates allelic multiplicity among detrimental alleles, and this is discussed in the context of clinical heterogeneity in simple Mendelian disorders.

}, keywords = {*Alleles, *Genetics, Medical, *Models, Genetic, *Selection, Genetic, Gene Frequency, Humans, Mutation, Probability}, isbn = {0002-9297 (Print)0002-9297 (Linking)}, author = {Hartl, D. L. and Campbell, R. B.} } @article {539391, title = {Defective Histone Transition during Spermiogenesis in Heterozygous SEGREGATION DISTORTER Males of DROSOPHILA MELANOGASTER}, journal = {Genetics}, volume = {101}, number = {1}, year = {1982}, note = {

Hauschteck-Jungen, EHartl, D Leng1982/05/01 00:00Genetics. 1982 May;101(1):57-69.

}, month = {May}, pages = {57-69}, abstract = {

Males of Drosophila melanogaster that are heterozygous for the segregation distorter (SD) chromosome produce a gross excess of SD-bearing offspring because most of the non-SD-bearing sperm are dysfunctional. These dysfunctional sperm exhibit abnormalities in chromatin condensation and compaction during spermiogenesis. Use of the fluorescent dye sulfoflavine, which is specific for basic proteins, has now revealed that the dysfunctional sperm are also defective in the normal transition from somatic to spermatid-specific histones.

}, isbn = {0016-6731 (Print)0016-6731 (Linking)}, author = {Hauschteck-Jungen, E. and Hartl, D. L.} } @article {539396, title = {The experimental assessment of fitness in Drosophila. I. Comparative measures of competitive reproductive success}, journal = {Genetics}, volume = {102}, number = {3}, year = {1982}, note = {

Haymer, D SHartl, D Leng1982/11/01 00:00Genetics. 1982 Nov;102(3):455-66.

}, month = {Nov}, pages = {455-66}, abstract = {

Strains of D. melanogaster, representing a range of genetic diversity, were systematically subjected to each of several techniques that have been devised to assess total or net fitness. All of these techniques operationally define fitness in terms of reproductive success under competitive conditions. For the set of strains tested, an excellent correlation was obtained between the competitive indices produced by two single-generation intraspecific competitions, despite fundamental differences in the strains used as competitive standards. The results of two interspecific tests were also correlated, but the intraspecific vs. interspecific test result comparisons ranged from highly significant to nonsignificant correlations. For the fitness estimates, the overall variances produced by the intraspecific tests were greater than those obtained in the interspecific competitions. No significant correlations were found between the results of a long-term (multi-generation) competitive assessment of fitness and any of the single-generation tests. Therefore, although all of these tests refer to a net parameter called "fitness", they are clearly not all measuring the same thing. Differences in the competitive interactions operative in each technique are suggested to account for these results.

}, isbn = {0016-6731 (Print)0016-6731 (Linking)}, author = {Haymer, D. S. and Hartl, D. L.} } @article {539136, title = {Polymorphism and selection}, journal = {Science}, volume = {213}, number = {4514}, year = {1981}, note = {

Hartl, D LengNew York, N.Y.1981/09/18 00:00Science. 1981 Sep 18;213(4514):1369-70.

}, month = {Sep 18}, pages = {1369-70}, isbn = {0036-8075 (Print)0036-8075 (Linking)}, author = {Hartl, D. L.} } @article {539241, title = {Potential for selection among nearly neutral allozymes of 6-phosphogluconate dehydrogenase in Escherichia coli}, journal = {Proc Natl Acad Sci U S A}, volume = {78}, number = {10}, year = {1981}, note = {

Hartl, D LDykhuizen, D EengGM 24886/GM/NIGMS NIH HHS/Research Support, U.S. Gov{\textquoteright}t, P.H.S.1981/10/01Proc Natl Acad Sci U S A. 1981 Oct;78(10):6344-8.

}, month = {Oct}, pages = {6344-8}, abstract = {

Six gnd alleles coding for naturally occurring allozymes of 6-phosphogluconate dehydrogenase [6-phospho-D-gluconate:NAD(P)+ 2-oxidoreductase, EC 1.1.1.43] have been transferred by transduction into the genetic background of Escherichia coli K-12 and examined for their selective effects in chemostats in which gluconate was limiting. Four of the alleles are evidently neutral or nearly neutral, inasmuch as their selective effects, if any, fall below the limit of resolution of the procedure--0.5\%/hr or about 1\% per generation. One allele is detrimental in limiting gluconate but not in limiting glucose or fructose. Another allele has a detrimental, density-dependent, epistatic interaction with tonA. We suggest that all six alleles are neutral or nearly neutral in natural populations but that they are not functionally equivalent; their functional differences are potentially important because they can become expressed as differences in fitness under the appropriate conditions of environment or genetic background. Under these conditions, otherwise neutral alleles can become subject to selection.

}, keywords = {*Selection, Genetic, Alleles, Computers, Escherichia coli/*enzymology/genetics, Isoenzymes/genetics, Phosphogluconate Dehydrogenase/*genetics, Species Specificity}, isbn = {0027-8424 (Print)0027-8424 (Linking)}, author = {Hartl, D. L. and Dykhuizen, D. E.} } @article {539131, title = {Genetic dissection of segregation distortion. III. Unequal recovery of reciprocal recombinants}, journal = {Genetics}, volume = {96}, number = {3}, year = {1980}, note = {

Hartl, D LengResearch Support, U.S. Gov{\textquoteright}t, Non-P.H.S.1980/11/01Genetics. 1980 Nov;96(3):685-96.

}, month = {Nov}, pages = {685-96}, abstract = {

The genetic structure of a segregation distorter chromosome (a derivative of SD-36) has been analyzed in a system in which recombination in the second chromosome is blocked by inversions except for the critical region around the centromeric heterochromatin. The results confirm the map order and characteristics of four loci known to be involved in segregation distortion, namely Sd, E(SD), Rspins, M(SD). However, SD-36 carries a fifth major locus involved in distortion. This locus is near pr in 2L and has the effect of enhancing the degree of distortion. In addition, reciprocal recombinant products from SD-36 are recovered unequally. All recombinants carrying the pr region from SD-36 seem also to carry Sd, although Sd has previously been mapped 1.6 units to the left of pr. Both the enhancement of distortion and the unequal recovery of reciprocal products can be explained if it is assumed that the new locus near pr in SD-36 is actually a duplication of Sd.

}, keywords = {*Recombination, Genetic, Animals, Chromosome Mapping, Chromosomes/ultrastructure, Crosses, Genetic, Drosophila melanogaster/*genetics, Female, Genes, Infertility, Male/*genetics, Male}, isbn = {0016-6731 (Print)0016-6731 (Linking)}, author = {Hartl, D. L.} } @article {538936, title = {Selective neutrality of 6PGD allozymes in E. coli and the effects of genetic background}, journal = {Genetics}, volume = {96}, number = {4}, year = {1980}, note = {

Dykhuizen, DHartl, D LengGM24886/GM/NIGMS NIH HHS/Research Support, U.S. Gov{\textquoteright}t, P.H.S.1980/12/01Genetics. 1980 Dec;96(4):801-17.

}, month = {Dec}, pages = {801-17}, abstract = {

We have used gluconate-limited chemostats to study selective differences between isogenic strains of Escherichia coli K12 into which four naturally occurring alleles coding for allozymes of 6-phosphogluconate dehydrogenase (6PGD) had been transferred. The limit of detectability of selection with our procedures is a selection coefficient of 0.5\%. In the normal E. coli K12 genetic background, all alleles are selectively neutral or nearly neutral. The absence of detectable selection does, however, depend on genetic background and on such environmental factors as cell density. In a genetic background containing a mutation that cuts off the alternative metabolic route for 6-phosphogluconate, selection between allozymes can be detected, and the selection is in the direction expected from the measured apparent Km values of the allozymes. Even when the alternative metabolic route is not blocked by mutation, one of the 6PGD allozymes has a detrimental, but density-dependent, interaction with a mutation conferring resistance to bacteriophage T5. In all cases, the observed selection is due to the allozymes themselves (or to associated regulatory elements), as the selection disappears when the chemostats are limited by a different carbon source (ribose plus succinate). Nevertheless, the four alleles do seem to be selectively neutral or nearly neutral in the normal E. coli K12 genetic background. Moreover, the distribution of allele frequencies in natural populations of E. coli is in accord with the expectations of selective neutrality.

}, keywords = {Alleles, Escherichia coli/*genetics, Isoenzymes/genetics, Kinetics, Phosphogluconate Dehydrogenase/*genetics/metabolism, Selection, Genetic}, isbn = {0016-6731 (Print)0016-6731 (Linking)}, author = {Dykhuizen, D. and Hartl, D. L.} } @article {539436, title = {Ultrastructural analysis of spermiogenesis in segregation distorter males of Drosophila melanogaster: the homozygotes}, journal = {Genetics}, volume = {96}, number = {3}, year = {1980}, note = {

Kettaneh, N PHartl, D Leng1980/11/01Genetics. 1980 Nov;96(3):665-83.

}, month = {Nov}, pages = {665-83}, abstract = {

We have studied spermiogenesis at the ultrastructural level in males of genotype SD(NH)-2/SD-72, which are nearly sterile owing to the dysfunction of virtually all of their sperm. Ultrastructural aspects of spermiogenesis in these homozygous SD males are qualitatively similar to those found among dysfunctional sperm produced by heterozygous SD males. In particular, chromatin condensation and/or compaction has been found to be abnormal. However, major quantitative differences have been noted. Most of the dysfunctional sperm in SD(NH)-2/SD-72 males are individualized and coiled. Then, the sperm evidently undergo degeneration, as few mature sperm can be found in the seminal vesicle. The relevance of these findings to the mechanism leading to near sterility in homozygous SD males is discussed.

}, keywords = {*Spermatogenesis, Animals, Drosophila melanogaster/*genetics, Homozygote, Infertility, Male/genetics, Male, Microscopy, Electron, Mutation, Spermatozoa/*ultrastructure}, isbn = {0016-6731 (Print)0016-6731 (Linking)}, author = {Kettaneh, N. P. and Hartl, D. L.} } @article {539386, title = {DNA Distribution in Spermatid Nuclei of Normal and Segregation Distorter Males of DROSOPHILA MELANOGASTER}, journal = {Genetics}, volume = {89}, number = {1}, year = {1978}, note = {

Hauschteck-Jungen, EHartl, D Leng1978/05/01 00:00Genetics. 1978 May;89(1):15-35.

}, month = {May}, pages = {15-35}, abstract = {

Using the DNA-specific dye BAO [2,5-bis-(4{\textquoteright}-aminophenyl-(1{\textquoteright})]-1,3,4-oxadiazol), we have examined spermiogenesis in wild-type males of Drosophila melanogaster and in males carrying various combinations of the Sd and Rsp mutations involved in segregation distortion. Wild-type strains, even those newly collected from nature, are heterogeneous with respect to the incidence of spermiogenic abnormalities, principally in having a variable number of spermatid nuclei per cyst that fail to undergo complete elongation. Among segregation distorter males, Rsp/Rsp homozygotes have the greatest incidence of nuclear nonelongation or incomplete elongation, Rsp/Rsp( +) heterozygotes are intermediate, while Rsp(+)/ Rsp(+) homozygotes have the least amount of abnormality. Indeed, Sd Rsp(+)/Sd(+)Rsp(+) males have significantly fewer spermiogenic aberrations than do wild-type strains.

}, isbn = {0016-6731 (Print)0016-6731 (Linking)}, author = {Hauschteck-Jungen, E. and Hartl, D. L.} } @article {538816, title = {Population Dynamics of the Segregation Distorter Polymorphism of DROSOPHILA MELANOGASTER}, journal = {Genetics}, volume = {89}, number = {1}, year = {1978}, note = {

Charlesworth, BHartl, D Leng1978/05/01 00:00Genetics. 1978 May;89(1):171-92.

}, month = {May}, pages = {171-92}, abstract = {

Two two-locus models of the population dynamics of the segregation distortion (SD) polymorphism of Drosophila melanogaster are described. One model is appropriate for understanding the population genetics of SD in nature, whereas the other is a special case appropriate for understanding an artificial population that has been extensively analysed. The models incorporate the general features of the Sd and Rsp loci which form the core of the SD system. It is shown that the SD polymorphism can be established only when there is sufficiently tight linkage between Sd and Rsp. An approximate treatment, valid for tight linkage, is given of all the equilibria of the system and their stabilities. It is shown that the observed composition of natural and artificial populations with respect to the Sd and Rsp loci is predicted well by the model, provided that restrictions are imposed on the fertilities of certain genotypes. Highly oscillatory paths towards equilibrium are usually to be expected on the basis of this model. The selection pressures on inversions introduced into this system are also investigated.

}, isbn = {0016-6731 (Print)0016-6731 (Linking)}, author = {Charlesworth, B. and Hartl, D. L.} } @article {539126, title = {Mechanism of a case of genetic coadaptation in populations of Drosophila melanogaster}, journal = {Proc Natl Acad Sci U S A}, volume = {74}, number = {1}, year = {1977}, note = {

Hartl, D LengResearch Support, U.S. Gov{\textquoteright}t, Non-P.H.S.Research Support, U.S. Gov{\textquoteright}t, P.H.S.1977/01/01Proc Natl Acad Sci U S A. 1977 Jan;74(1):324-8.

}, month = {Jan}, pages = {324-8}, abstract = {

A cryptic polymorphism found in natrual populations of Drosophila melanogaster has been examined in an artificial population maintained for over 200 generations. The polymorphism is selected because it is insensitive to the segregation distorter phenomenon, and it thereby largely preserves the Mendelian rules of segregation. Segregation distorter chromosomes and the cryptic polymorphism form part of a coadapted complex which is associated with linkage disequilibrium in natrual populations.

}, keywords = {*Gene Frequency, *Polymorphism, Genetic, *Recombination, Genetic, *Selection, Genetic, Animals, Drosophila melanogaster/*physiology, Female, Genes, Genetic Linkage, Heterozygote, Male}, isbn = {0027-8424 (Print)0027-8424 (Linking)}, author = {Hartl, D. L.} } @article {539121, title = {Mutation-selection balance with stochastic selection}, journal = {Genetics}, volume = {86}, number = {3}, year = {1977}, note = {

Hartl, D LengResearch Support, U.S. Gov{\textquoteright}t, Non-P.H.S.Research Support, U.S. Gov{\textquoteright}t, P.H.S.1977/07/01Genetics. 1977 Jul;86(3):687-96.

}, month = {Jul}, pages = {687-96}, abstract = {

Diffusion theory has been used to analyze a model of mutation-selection balance in which the selection process is assumed to be stochastic in time. The limiting outcome of the mutation-stochastic selection process is determined qualitatively by the geometric mean fitnesses of the genotypes, and the conditions for fixation or polymorphism are similar to those that determine the outcome of the mutation-selection process when selection is constant. However, in the case of a completely recessive allele, detailed numerical study of the polymorphism associated with stochastic selection has shown that the average allele frequency maintained is greater than the equilibrium frequency expected when selection is constant, even when the geometric mean fitness of the recessive homozygotes is identical in the stochastic and deterministic models. Thus, allele frequencies in natural populations that are too high to be plausibly explained by a balance between mutation and constant selection can be accounted for if selection is stochastic.

}, keywords = {*Mutation, *Selection, Genetic, Alleles, Animals, Gene Frequency, Genes, Recessive, Genotype, Models, Biological, Polymorphism, Genetic, Stochastic Processes}, isbn = {0016-6731 (Print)0016-6731 (Linking)}, author = {Hartl, D. L.} } @article {538971, title = {Cytogenetic analysis of homozygous segregation distorter males of Drosophila melanogaster}, journal = {Can J Genet Cytol}, volume = {18}, number = {2}, year = {1976}, note = {

Erickson, JHartl, D LengCANADA1976/06/01Can J Genet Cytol. 1976 Jun;18(2):287-96.

}, month = {Jun}, pages = {287-96}, abstract = {

Certain homozygous SD males are nearly sterile. Sterility is not due to aneuploid gametes--no significant second chromosome nondisjunction was found in matings to attached-2 and mei-S332 females. Some fourth chromosome aneuploidy was observed here, and in the cytological work. Otherwise, cytology of the meiotic divisions was essentially normal. Early spermatid bundles are normal, sperm head counts approximating the normal 64. In the later, coiled bundle stage, one observes less than 30 heads many of which are grossly abnormal: twisted, club-like, or globular. In double mating experiments, SD/SD sperm did not displace normal sperm introduced first. In the reverse experiment, sperm (or fluid) from SD/SD males markedly reduced capacity of the females to store and utilize sperm from normal males, as scored from progeny and by counts of stored sperm. No sperm were seen in the storage organs of females imseminated first by SD/SD then by normal males. Many females refuse such a second mating. Our observations are quantitatively different from those with heterozygous SD males, but qualitatively similar, supporting the view that the near sterility of homozygous SD males arises from a mechanism of sperm dysfunction like that in SD/+ males.

}, keywords = {*Chromosome Aberrations, *Drosophila melanogaster, *Meiosis, *Spermatogenesis, Animals, Fertility, Homozygote, Male, Recombination, Genetic, Sperm Head/ultrastructure}, isbn = {0008-4093 (Print)0008-4093 (Linking)}, author = {Erickson, J. and Hartl, D. L.} } @article {538841, title = {Estimation of inbreeding by random walks in pedigrees}, journal = {Theor Appl Genet}, volume = {48}, number = {4}, year = {1976}, note = {

Cook, R DHartl, D LengGermany1976/07/01 00:00Theor Appl Genet. 1976 Jul;48(4):171-8. doi: 10.1007/BF00527368.

}, month = {Jul}, pages = {171-8}, abstract = {

Wright and McPhee (1925) suggested a method of estimating the inbreeding coefficient of an individual based on the probability that a pair of lineages traced randomly, one through the maternal line and one through the paternal line, both contain a common ancestor. (One-half of this probability is an unbiased estimate of the inbreeding coefficient). In their procedure, maternal and paternal lines are chosen in pairs, and comparisons are made only between the lines in a pair. A more efficient procedure is to compare every maternal line with every paternal line, a procedure used by Robertson and Mason (1954). In this paper we provide estimates of the sampling variance of the inbreeding coefficient as estimated by the multiple comparison method, and we examine the relative efficiency of this method and the Wright-McPhee procedure. Formulae are also provided for ascertaining the optimal sampling method for estimating the average inbreeding coefficient of a group or herd.

}, isbn = {0040-5752 (Print)0040-5752 (Linking)}, author = {Cook, R. D. and Hartl, D. L.} } @article {539431, title = {Histone transition during spermiogenesis is absent in segregation distorter males of Drosophila melanogaster}, journal = {Science}, volume = {193}, number = {4257}, year = {1976}, note = {

Kettaneh, N PHartl, D LengResearch Support, U.S. Gov{\textquoteright}t, Non-P.H.S.Research Support, U.S. Gov{\textquoteright}t, P.H.S.New York, N.Y.1976/09/10Science. 1976 Sep 10;193(4257):1020-1.

}, month = {Sep 10}, pages = {1020-1}, abstract = {

Males homozygous for the segregation distorter chromosome are often sterile or nearly sterile as a result of the dysfunction of virtually all their sperm. Spermatid bundles from such males do not exhibit the normal transition from lysine-rich to arginine-rich histones.

}, keywords = {*Spermatogenesis, Animals, Chromosome Aberrations/*metabolism, Chromosome Disorders, Drosophila melanogaster/metabolism, Histones/*metabolism, Infertility, Male/genetics, Male, Spermatids/metabolism}, isbn = {0036-8075 (Print)0036-8075 (Linking)}, author = {Kettaneh, N. P. and Hartl, D. L.} } @article {539116, title = {Stochastic selection in both haplophase and diplophase}, journal = {J Math Biol}, volume = {3}, number = {3-4}, year = {1976}, note = {

Hartl, D LengGERMANY, WEST1976/11/25J Math Biol. 1976 Nov 25;3(3-4):263-9.

}, month = {Nov 25}, pages = {263-9}, abstract = {

A population genetic model incorporating the evolutionary forces of zygotic selection, gametic selection and non-Mendelian segregation has been analyzed for the case in which all selection coefficients and the segregation parameter are assumed to be random variables that are uncorrelated from generation to generation. The diffusion approximation of the model is developed, and the subsequent analysis shows that one of four limiting outcomes of the stochastic process may obtain--an allele may be fixed or lost almost surely and irrespective of the initial gene frequency, the gene frequency may converge to a unique stationary distribution, or an allele may be fixed or lost with probabilities depending on the initial gene frequency. These outcomes correspond rather closely with the possible outcomes of the deterministic model--fixation or loss of an allele, convergence to a stable equilibrium, or the existence of an unstable equilibrium.

}, keywords = {*Diploidy, *Genetics, Population, *Haploidy, *Models, Biological, *Selection, Genetic, Alleles, Female, Gene Frequency, Zygote}, isbn = {0303-6812 (Print)0303-6812 (Linking)}, author = {Hartl, D. L.} } @article {539236, title = {Adaptive significance of vegetative incompatibility in Neurospora crassa}, journal = {Genetics}, volume = {81}, number = {3}, year = {1975}, note = {

Hartl, D LDempster, E RBrown, S WengResearch Support, U.S. Gov{\textquoteright}t, P.H.S.1975/11/01Genetics. 1975 Nov;81(3):553-69.

}, month = {Nov}, pages = {553-69}, abstract = {

Certain features reminiscent of sexuality occur in the vegetative life cycle of some filamentous fungi such as Neurospora crassa. Hyphal fusions can occur between genetically different individuals, thereby endowing the new composite mycelium, a heterokaryon, with some of the advantages of heterozygosity usually associated with diploid organisms. In N. crassa, however, there are a number of incompatibility loci which prevent formation of heterokaryons unless the alleles at the incompatibility loci are identical in the two mycelia. The selection pressures that maintain incompatibility polymorphisms are not known. We suggest here that they are maintained because they prevent a kind of exploitation of heterokaryons by nuclei that are nonadaptive in homokaryons but that enjoy a proliferative advantage over other nuclei in heterokaryons. A mathematical model that abstracts the major features of the vegetative life cycle of Neurosopra crassa has been developed, and the action of selection in this model and various extensions of it is such as to maintain polymorphisms of vegetative incompatibility factors.

}, keywords = {*Adaptation, Biological, *Models, Biological, Alleles, Neurospora crassa/*physiology, Neurospora/*physiology, Polymorphism, Genetic}, isbn = {0016-6731 (Print)0016-6731 (Linking)}, author = {Hartl, D. L. and Dempster, E. R. and Brown, S. W.} } @article {539106, title = {Genetic dissection of segregation distortion II. Mechanism of suppression of distortion by certain inversions}, journal = {Genetics}, number = {3}, year = {1975}, note = {

Hartl, D Leng1975/07/01Genetics. 1975 Jul;(3):539-47.

}, month = {Jul}, pages = {539-47}, abstract = {

In(2L+2R)Cgamma and In(2LR)Pm2 are inversion-bearing chromosomes, the former carrying a paracentric inversion in each arm and the latter carrying a long pericentric. Both chromosomes produce normal segregation ratios when present in heterozygous males with certain segregation distorter chromosomes. The apparent suppression of distortion by these chromosomes was long attributed to a failure of synapsis, but this hypothesis has fallen out of favor recently because a large number of chromosome aberrations, particularly translocations and inversions, suppress distortion even though their breakpoints fall into no recognizable pattern. Although failure of synapsis does not appear to be the mechanism of suppression of distortion, what is responsible for the suppression remains unknown. In this paper it is shown that In(2L+2R)Cgamma and In(2LR)Pm2 suppress segregation distortion because they carry Rsp, a component of the segregation distorter system that renders a chromosome insensitive to distortion. Both chromosomes induce "suicide" of chromosomes carrying Sd Rsp+.

}, keywords = {*Chromosome Aberrations, *Chromosome Inversion, *Drosophila melanogaster, *Meiosis, *Recombination, Genetic, Animals, Chromosomes, Female, Genes, Genetic Linkage, Genotype, Male}, isbn = {0016-6731 (Print)0016-6731 (Linking)}, author = {Hartl, D. L.} } @article {539111, title = {Modifier theory and meiotic drive}, journal = {Theor Popul Biol}, volume = {7}, number = {2}, year = {1975}, note = {

Hartl, D LengResearch Support, U.S. Gov{\textquoteright}t, Non-P.H.S.Research Support, U.S. Gov{\textquoteright}t, P.H.S.1975/04/01Theor Popul Biol. 1975 Apr;7(2):168-74.

}, month = {Apr}, pages = {168-74}, keywords = {*Alleles, *Meiosis, *Models, Biological, Genes, Lethal, Genes, Recessive, Genetic Linkage, Selection, Genetic, Suppression, Genetic}, isbn = {0040-5809 (Print)0040-5809 (Linking)}, author = {Hartl, D. L.} } @article {539006, title = {Regulation of newly evolved enzymes. II. The ebg repressor}, journal = {Genetics}, volume = {81}, number = {3}, year = {1975}, note = {

Gall, B GHartl, D LengResearch Support, U.S. Gov{\textquoteright}t, P.H.S.1975/11/01Genetics. 1975 Nov;81(3):427-35.

}, month = {Nov}, pages = {427-35}, abstract = {

The ebg (evolved beta-galactosidase) regulatory locus has been mapped. The map order is argG-ebgA-ebgR-tolC-metC, and there is 1.6\% recombination between ebgR and ebgA. Studies with ebgR-/ebgR+ merdiploids have shown that ebgR- is recessive, and it is concluded that the synthesis of ebg enzyme is under negative control.

}, keywords = {*Chromosome Mapping, *Escherichia coli, *Galactosidases, *Genes, Regulator, Chromosomes, Bacterial, Genes, Recessive}, isbn = {0016-6731 (Print)0016-6731 (Linking)}, author = {Gall, B. G. and Hartl, D. L.} } @article {539101, title = {Genetic dissection of segregation distortion. I. Suicide combinations of SD genes}, journal = {Genetics}, volume = {76}, number = {3}, year = {1974}, note = {

Hartl, D Leng1974/03/01Genetics. 1974 Mar;76(3):477-86.

}, month = {Mar}, pages = {477-86}, abstract = {

Two major loci in the Tft-cn region of an SD chromosome have been separated by recombination and identified. The allele at the left-hand locus on an SD chromosome is called Sd; the allele at the right-hand locus is called Rsp. Both Sd and Rsp are necessary to bring about a distortion of the segregation ratio in heterozygous SD males, although the particular degree of distortion exhibited by an SD chromosome is influenced by the constellation of polygenic modifiers of SD in the genome. The coupling phase of the alleles, Sd Rsp/Sd(+)Rsp(+), produces about 89-90\% of Sd Resp-bearing progeny. The repulsion phase, Sd Rsp(+)/Sd(+)Rsp, produces 10-20\% of Sd Rsp(+)-bearing progeny. No coupling-repulsion effects between Sd and Rsp are apparent.

}, keywords = {*Chromosome Mapping, *Drosophila melanogaster, *Genes, *Recombination, Genetic, Alleles, Animals, Chromosome Aberrations, Female, Heterozygote, Male, Meiosis, Mutation, Phenotype}, isbn = {0016-6731 (Print)0016-6731 (Linking)}, author = {Hartl, D. L.} } @article {539056, title = {Regulation of newly evolved enzymes. I. Selection of a novel lactase regulated by lactose in Escherichia coli}, journal = {Genetics}, volume = {76}, number = {3}, year = {1974}, note = {

Hall, B GHartl, D Leng1974/03/01Genetics. 1974 Mar;76(3):391-400.

}, month = {Mar}, pages = {391-400}, abstract = {

Thirty-four lactose-utilizing strains of E. coli were selected from a lac Z deletion strain. In 31 of these, the synthesis of the newly evolved lactase is regulated by lactose. The lactase activity in all the strains is indistinguishable from the ebg(+) activity identified by Campbell, Lengyel and Langridge (1973).

}, keywords = {*Operon, Bacterial Proteins/biosynthesis, Culture Media, Enzyme Induction, Escherichia coli/*enzymology, Galactosidases/*biosynthesis, Lactose/*metabolism, Temperature, Time Factors}, isbn = {0016-6731 (Print)0016-6731 (Linking)}, author = {Hall, B. G. and Hartl, D. L.} } @article {539276, title = {Second naturally occurring beta-galactosidase in E. coli}, journal = {Nature}, volume = {248}, number = {5444}, year = {1974}, note = {

Hartl, D LHall, B GengENGLAND1974/03/08Nature. 1974 Mar 8;248(5444):152-3.

}, month = {Mar 8}, pages = {152-3}, keywords = {Chromosome Mapping, Crosses, Genetic, Enzyme Induction, Escherichia coli/*enzymology/metabolism, Galactosidases/biosynthesis/*metabolism, Genes, Lactose/metabolism/pharmacology, Mutation, Recombination, Genetic}, isbn = {0028-0836 (Print)0028-0836 (Linking)}, author = {Hartl, D. L. and Hall, B. G.} } @article {539096, title = {Complementation analysis of male fertility among the segregation distorter chromosomes of Drosophila melanogaster}, journal = {Genetics}, volume = {73}, number = {4}, year = {1973}, note = {

Hartl, D Leng1973/04/01Genetics. 1973 Apr;73(4):613-29.

}, month = {Apr}, pages = {613-29}, abstract = {

The fecundities of 55 genotypes of the form SD(i)/SD(j) generated by 11 different SD chromosomes have been examined. Five of the genotypes are lethal The fecundities of the rest fall into a pattern of fertility and sterility that is highly suggestive of intracistronic complementation. The complementation leading to male fertility is only partial complementation: the fecundity of most fertile genotypes is less than half that of controls. The three components of the SD system, the Sd locus, the Ac locus, and the modifiers in 2R, were examined separately, and it appears that the complementation is a phenomenon associated with the Sd locus. A hypothesis of the molecular events involved in segregation distortion is formulated in the light of these observations. The model is based on the assumption that the Sd locus produces a multimeric molecule that regulates the activity of the Ac(=Rsp) locus during spermatogenesis.

}, keywords = {*Chromosomes, *Drosophila melanogaster, *Fertility, Alleles, Animals, Genes, Lethal, Genotype, Male, Models, Biological, Spermatogenesis}, isbn = {0016-6731 (Print)0016-6731 (Linking)}, author = {Hartl, D. L.} } @article {539091, title = {The Mechanism of a Brooding Effect Associated with Segregation Distortion in DROSOPHILA MELANOGASTER}, journal = {Genetics}, volume = {74}, number = {4}, year = {1973}, note = {

Hartl, D Leng1973/08/01 00:00Genetics. 1973 Aug;74(4):619-31.

}, month = {Aug}, pages = {619-31}, abstract = {

The recovery of the SD chromosome from a heterozygous SD male increases with brood. This is independent of the age of the female, occurs during the time the sperm are stored in the females, disappears when the segregation distortion is suppressed, and is temperature-sensitive-temperature shocks above or below 25 degrees C applied to the mature sperm both tend to accelerate the increase in the recovery of SD. All this suggests the existence of a class of sperm affected by SD in which the sperm are able to fertilize eggs for a short time following ejaculation but become dysfunctional thereafter.

}, isbn = {0016-6731 (Print)0016-6731 (Linking)}, author = {Hartl, D. L.} } @article {539086, title = {Population dynamics of sperm and pollen killers}, journal = {Theor Appl Genet}, volume = {42}, number = {2}, year = {1972}, note = {

Hartl, D LengGermany1972/01/01 00:00Theor Appl Genet. 1972 Jan;42(2):81-8. doi: 10.1007/BF00277948.

}, month = {Jan}, pages = {81-8}, abstract = {

A model of segregation distortion is assumed in which the action of the distorter when heterozygous is to render dysfunctional those gametes that carry its allele. Two gamete killers when homozygous are assumed to distort each other. Individuals that carry the gamete killer suffer a reduction in the number of functional gametes they produce, but this deleterious effect is counterbalanced by the segregation ratio advantage of the distorter. The dynamics of such a system are analyzed in terms of a generalized fecundity function, which is defined as a function which assigns to any individual his relative fecundity in terms of the fraction of functional gametes he produces. Three general classes of fecundity functions are considered: (a) proportionality, in which the relative fecundity of an individual is proportional to the fraction of functional gametes he produces, (b) compensation, in which the relative fecundity of an individual is always greater than the fraction of functional gametes he produces, and (c) mass action, in which the relative fecundity of an individual is less than or greater than the fraction of functional gametes he produces according to whether the fraction of functional gametes is less than or greater than some threshold. In case (a) all gamete killers are always at neutral equilibria and gene frequency changes at the locus are governed by random drift. In case (b) all gamete killers will be fixed if the fecundity function is such that its second derivative is negative, whenever its argument is greater than one-half. And in case (c) some gamete killers will converge to stable equilibria, others will be fixed. If a gamete killer is homozygous lethal it will almost always converge to a stable equilibrium.

}, isbn = {0040-5752 (Print)0040-5752 (Linking)}, author = {Hartl, D. L.} } @article {538821, title = {Sperm preference in Drosophila melanogaster}, journal = {Genetics}, volume = {71}, number = {3}, year = {1972}, note = {

Childress, DHartl, D Leng1972/07/01Genetics. 1972 Jul;71(3):417-27.

}, month = {Jul}, pages = {417-27}, keywords = {*Drosophila melanogaster, *Fertilization, *Spermatozoa, Age Factors, Animals, Chromosome Aberrations, Crosses, Genetic, Female, Genotype, Male}, isbn = {0016-6731 (Print)0016-6731 (Linking)}, author = {Childress, D. and Hartl, D. L.} } @article {539081, title = {Recurrence risks for germinal mosaics}, journal = {Am J Hum Genet}, volume = {23}, number = {2}, year = {1971}, note = {

Hartl, D Leng1971/03/01Am J Hum Genet. 1971 Mar;23(2):124-34.

}, month = {Mar}, pages = {124-34}, keywords = {*Chromosome Aberrations, *Mosaicism, Eugenics, Genes, Dominant, Genetic Diseases, Inborn/prevention \& control, Germ Cells/*cytology, Humans, Mathematics, Models, Biological, Mutation}, isbn = {0002-9297 (Print)0002-9297 (Linking)}, author = {Hartl, D. L.} } @article {539271, title = {Genetic studies of germinal mosaicism in Drosophila melanogaster using the mutable wc gene}, journal = {Genetics}, volume = {65}, number = {3}, year = {1970}, note = {

Hartl, D LGreen, M Meng1970/07/01Genetics. 1970 Jul;65(3):449-56.

}, month = {Jul}, pages = {449-56}, keywords = {*Germ Cells, *Mosaicism, *Mutation, Aging, Animals, Cell Differentiation, Cell Division, Drosophila, Female, Male, Spermatozoa, Testis/*cytology}, isbn = {0016-6731 (Print)0016-6731 (Linking)}, author = {Hartl, D. L. and Green, M. M.} } @article {539076, title = {A mathematical model for recessive lethal segregation distorters with differential viabilities in the sexes}, journal = {Genetics}, volume = {66}, number = {1}, year = {1970}, note = {

Hartl, D Leng1970/09/01Genetics. 1970 Sep;66(1):147-63.

}, month = {Sep}, pages = {147-63}, keywords = {*Genes, Lethal, *Genes, Recessive, *Genetics, Population, *Meiosis, *Sex, Animals, Drosophila, Gene Frequency, Hybrid Vigor, Models, Biological, Selection, Genetic}, isbn = {0016-6731 (Print)0016-6731 (Linking)}, author = {Hartl, D. L.} } @article {539071, title = {Meiotic drive in natural populations of Drosophila melanogaster. IX. Suppressors of segregation distorter in wild populations}, journal = {Can J Genet Cytol}, volume = {12}, number = {3}, year = {1970}, note = {

Hartl, D LengCANADA1970/09/01Can J Genet Cytol. 1970 Sep;12(3):594-600.

}, month = {Sep}, pages = {594-600}, keywords = {*Gene Frequency, *Meiosis, *Suppression, Genetic, Animals, Drosophila, Female, Genes, Dominant, Male, Sex Chromosomes}, isbn = {0008-4093 (Print)0008-4093 (Linking)}, author = {Hartl, D. L.} } @article {539221, title = {The origin of male haploid genetic systems and their expected sex ratio}, journal = {Theor Popul Biol}, volume = {1}, number = {2}, year = {1970}, note = {

Hartl, D LBrown, S Weng1970/08/01Theor Popul Biol. 1970 Aug;1(2):165-90.

}, month = {Aug}, pages = {165-90}, keywords = {*Genetics, Population, *Models, Biological, *Parthenogenesis, *Sex Ratio, Environment, Haploidy, Male, Mathematics, Mutation, Spermatogenesis}, isbn = {0040-5809 (Print)0040-5809 (Linking)}, author = {Hartl, D. L. and Brown, S. W.} } @article {539066, title = {Dysfunctional sperm production in Drosophila melanogaster males homozygous for the segregation distorter elements}, journal = {Proc Natl Acad Sci U S A}, volume = {63}, number = {3}, year = {1969}, note = {

Hartl, D Leng1969/07/01Proc Natl Acad Sci U S A. 1969 Jul;63(3):782-9.

}, month = {Jul}, pages = {782-9}, abstract = {

Drosophila males heterozygous for the segregation distorter chromosome show a reduction in fecundity which is correlated with the degree of distortion of their segregation ratio. When males are made homozygous for the segregation distorter elements, their fecundity is lowered to just that extent expected if each SD were independently causing the sperms carrying the other to dysfunction. In three cases tested, Sd Ac/Ac, Sd Ac/Sd Ac, and Sd Ac St/Sd Ac St, the fecundity of the males is consistent with the dysfunction model, whereas the females are normal. The Sd Ac St/Sd Ac St males are almost completely sterile. They do produce sperms, however, which are motile and which look morphologically normal in the phase contrast microscope. They are transferred to the female during copulation and are stored in apparently normal numbers in the seminal receptacle and spermathecae.

}, keywords = {*Homozygote, Animals, Drosophila, Infertility, Male/*genetics, Male, Microscopy, Phase-Contrast, Models, Biological, Spermatozoa/cytology/*physiopathology}, isbn = {0027-8424 (Print)0027-8424 (Linking)}, author = {Hartl, D. L.} } @article {539331, title = {Phenogram enumeration: the number of regular genotype-phenotype correspondences in genetic systems}, journal = {J Theor Biol}, volume = {20}, number = {2}, year = {1968}, note = {

Hartl, D LMaruyama, TengENGLAND1968/08/01J Theor Biol. 1968 Aug;20(2):129-63.

}, month = {Aug}, pages = {129-63}, keywords = {*Genotype, *Phenotype, Alleles, Blood Group Antigens, Chromosome Mapping, Computers, Diploidy, Haploidy, Heterozygote, Homozygote, Mathematics, Models, Biological, Polyploidy}, isbn = {0022-5193 (Print)0022-5193 (Linking)}, author = {Hartl, D. L. and Maruyama, T.} } @article {539281, title = {Evidence for sperm dysfunction as the mechanism of segregation distortion in Drosophila melanogaster}, journal = {Proc Natl Acad Sci U S A}, volume = {58}, number = {6}, year = {1967}, note = {

Hartl, D LHiraizumi, YCrow, J Feng1967/12/01Proc Natl Acad Sci U S A. 1967 Dec;58(6):2240-5.

}, month = {Dec}, pages = {2240-5}, keywords = {*Chromosomes, *Genetics, *Spermatozoa, Animals, Drosophila, Female, Fertility, Male, Meiosis}, isbn = {0027-8424 (Print)0027-8424 (Linking)}, author = {Hartl, D. L. and Hiraizumi, Y. and Crow, J. F.} }