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Search Results: 1 - 10 of 237692 matches for " Daniel L. Hartl "
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Genome Organization and Gene Expression Shape the Transposable Element Distribution in the Drosophila melanogaster Euchromatin
Pierre Fontanillas,Daniel L Hartl,Max Reuter
PLOS Genetics , 2007, DOI: 10.1371/journal.pgen.0030210
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.
The latest buzz in comparative genomics
Rob J Kulathinal, Daniel L Hartl
Genome Biology , 2004, DOI: 10.1186/gb-2005-6-1-201
Abstract: The genus Drosophila is no stranger to the spotlight. With over 2,000 known species, Drosophila offers a useful investigative platform for biologists of all sorts. Its interesting and diverse biology and ease of breeding in a variety of conditions has made Drosophila a favorite laboratory model organism. As the leading player in its genus, Drosophila melanogaster has enjoyed a long and distinguished tenure in biological research, particularly because it has become an indispensable model system for genetics. Ultimately, D. melanogaster was among the first eukaryotes to be sequenced [1] and the genome sequence triggered much excitement in terms of novel approaches and new-found collaborations.Although bottled 'populations' of D. melanogaster genetic mutants quickly became the standard resource for geneticists, these lab strains were at first not useful to those researchers studying evolutionary processes. D. melanogaster and its sibling species Drosophila simulans, although currently distributed worldwide, arrived only recently from Africa and are, therefore, not the most ideal material for understanding historical mechanisms. To study a more natural situation, Theodosius Dobzhansky, a naturalist and geneticist, began to work with the then little-known species Drosophila pseudoobscura, whose natural habitat range largely covers the western part of North America. Dobzhansky believed that the genetics of speciation could be successfully understood only by studying natural genetic variation within populations, and he and others spent years developing genetic tools for D. pseudoobscura. Dobzhansky thought of D. melanogaster as a 'garbage species' whose human commensal activity was problematic for investigating microevolutionary processes involved in reproductive isolation. Much of his species choice was fortuitous - Dobzhansky taught at Caltech (Pasadena, USA) and was captivated by the large and ecologically stable levels of variation that he found among chromosome invers
Bayesian analysis of gene expression levels: statistical quantification of relative mRNA level across multiple strains or treatments
Jeffrey P Townsend, Daniel L Hartl
Genome Biology , 2002, DOI: 10.1186/gb-2002-3-12-research0071
Abstract: 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 'fold-change' that are not statistically significantly different, and genes differentially regulated in quantitatively unanticipated ways.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.Methods for analysis of cDNA microarray data include those that cluster hierarchically [1] by principles of self-organization [2] or by k-means [3]. These methods yield enormous amounts of information about similarities of cell state and coordination of gene regulation, and are useful for grouping genes or transcriptional profiles by similarity. They have the limitation that although experimental replication enhances the significance of groupings observed, the groupings do not inherently quantify signal and noise. A fold-value cutoff originally was used for this purpose [4], and held double duty as a signifier of true signal and a boundary beyond which observed fold-measures were considered to be reflective of actual fold-change. Other approaches use likelihood-based methods [5,6] to obtain P-values for gene expression differences in replicated comparisons. These methods m
Fitness Trade-Offs in the Evolution of Dihydrofolate Reductase and Drug Resistance in Plasmodium falciparum
Marna S. Costanzo,Kyle M. Brown,Daniel L. Hartl
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0019636
Abstract: 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.
Model transcriptional networks with continuously varying expression levels
Mauricio O Carneiro, Clifford H Taubes, Daniel L Hartl
BMC Evolutionary Biology , 2011, DOI: 10.1186/1471-2148-11-363
Abstract: 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.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.In the approximately ten years since the completion of the draft sequence of the human genome, researchers have become increasingly attuned to the many layers of complexity that underlie the mechanisms of life [1]. Many new genes have been identified for transcription factors whose role is to activate or inhibit the production of other genes. The interplay between mutually interacting transcription factors defines a regulatory network that dictates the levels of RNA transcripts, signaling proteins, enzymes and other gene products. Such networks have emergent properties that are essential in every living system[2].Understanding the organization and evolution of these networks has been a challenge because of their complexity. Experimental studies have been able to identify important roles of interacting regulatory networks, such as the ability of yeast to respond to environmental changes[3], the specification of the endomesoderm in sea urchin embryos[4], and dorsal-ventral patterning in the Drosophila embryo[5]. Although early studies of quantitative traits also revealed clues about such networks[6], it has not been generally feasible to address the more general questions how they originate and evolve.A mathematical model of mutually interacting transcription factors was first
Population Genomics of Inversion Polymorphisms in Drosophila melanogaster
Russell B. Corbett-Detig ,Daniel L. Hartl
PLOS Genetics , 2012, DOI: 10.1371/journal.pgen.1003056
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'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 ~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.
Adaptive Landscape by Environment Interactions Dictate Evolutionary Dynamics in Models of Drug Resistance
C. Brandon Ogbunugafor?,C. Scott Wylie?,Ibrahim Diakite?,Daniel M. Weinreich?,Daniel L. Hartl
PLOS Computational Biology , 2016, DOI: 10.1371/journal.pcbi.1004710
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—drug concentration and drug type. We do so by studying the resistance mediated by Plasmodium falciparum dihydrofolate reductase (DHFR) to two related inhibitors—pyrimethamine and cycloguanil—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 “forks in the road” 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.
Novel Genes from Formation to Function
Rita Ponce,Lene Martinsen,Luís M. Vicente,Daniel L. Hartl
International Journal of Evolutionary Biology , 2012, DOI: 10.1155/2012/821645
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. 1. Introduction The availability of complete genome sequences allows the comparison of genomes, thus revealing the differences in gene complement and demonstrating the nature of the changes that occur in the evolution of genomes. In particular, genomic analysis showed that more than one-third of the eukaryotic genome is composed of gene duplications and gene families (e.g., [1–4]), highlighting the prominence of duplications in the evolution of genomes. The study of whole genomes also allows an analysis of the rates and dynamics of duplications as well as the divergence and silencing of duplicates (e.g., [5–7]). Moreover, evidence indicates that the rates of duplication are extremely high and of the same order of magnitude as the rate of mutation per nucleotide; for example, the frequency of duplication for coding genes was found to be 0.01 per gene per million years [8] and for internal duplications of gene segments, 0.001–0.013 duplications/gene per million years [9]. The fates of gene duplicates can be very different according to the mutations they undergo and the selective pressures they are under. After a gene is duplicated, the most common fate seems to be the loss of function of one copy by the acquisition of degenerative mutations, while the other copy retains the original function. The originally identical copies can also both be maintained in the genome, allowing a higher production of the corresponding RNA or protein. Subsequent mutation by retrotransposon insertion into one of the copies can affect adaptive evolution because the effect on the phenotype can in some cases be beneficial to the organism [10]. Partial gene duplications can also occur, and if the duplicated part involves a structural or functional domain the new gene can increase the functional complexity of the encoded protein. It has also been proposed that if two copies of
Ribosomal DNA Deletions Modulate Genome-Wide Gene Expression: “rDNA–Sensitive” Genes and Natural Variation
Silvana Paredes,Alan T. Branco,Daniel L. Hartl,Keith A. Maggert ,Bernardo Lemos
PLOS Genetics , 2011, DOI: 10.1371/journal.pgen.1001376
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.
A sex-ratio Meiotic Drive System in Drosophila simulans. II: An X-linked Distorter
Yun Tao,Luciana Araripe,Sarah B. Kingan,Yeyan Ke,Hailian Xiao,Daniel L. Hartl
PLOS Biology , 2012, DOI: 10.1371/journal.pbio.0050293
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'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.
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