The Experts below are selected from a list of 16563 Experts worldwide ranked by ideXlab platform
Austin L. Hughes - One of the best experts on this subject based on the ideXlab platform.
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Ongoing Purifying Selection on intergenic spacers in group A streptococcus.
Infection genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases, 2010Co-Authors: Haiwei Luo, Robert Friedman, Jijun Tang, Austin L. HughesAbstract:Bacterial intergenic spacers are non-coding genomic regions enriched with cis-regulatory elements for gene expression. A population genetics approach was used to investigate the evolutionary force shaping the genetic diversity of intergenic spacers among 13 genomes of group A streptococcus (GAS). Analysis of 590 genes and their linked 5' intergenic spacers showed reduced nucleotide diversity in spacers compared to synonymous nucleotide diversity in protein-coding regions, suggestive of past Purifying Selection on spacers. Certain spacers showed elevated nucleotide diversity indicative of past homologous recombination with divergent genotypes. In addition, analysis of the difference between mean nucleotide difference and number of segregating sites showed evidence of an excess of rare variants both at nonsynonymous sites in genes and at sites in spacers, which is evidence that there are numerous slightly deleterious variants in GAS populations with potential effects on both protein sequences and gene expression.
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Relaxation of Purifying Selection on the SAD lineage of live attenuated oral vaccines for rabies virus.
Infection genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases, 2009Co-Authors: Austin L. HughesAbstract:Analysis of patterns of nucleotide sequence diversity in wild-type rabies virus (RABV) genomes and in the SAD live attenuated oral vaccine lineage was used to test for the relaxation of Purifying Selection in the latter and provide evidence regarding the genomic regions where such relaxation of Selection occurs. The wild-type sequences showed evidence of strong past and ongoing Purifying Selection both on nonsynonymous sites in coding regions and on non-coding regions, particularly the start, end and 5' UTR regions. SAD vaccine sequences showed a relaxation of Purifying Selection at nonsynonymous sites in coding regions, resulting a substantial number of amino acid sequence polymorphisms at sites that were invariant in the wild-type sequences. Moreover, SAD vaccine sequences showed high levels of mutation accumulation in the non-coding regions that were most conserved in the wild-type sequences. Understanding the biological effects of the unique mutations accumulated in the vaccine lineage is important because of their potential effects on antigenicity and effectiveness of the vaccine.
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relaxation of Purifying Selection on live attenuated vaccine strains of the family paramyxoviridae
Vaccine, 2009Co-Authors: Austin L. HughesAbstract:In wild-type sequences of three paramyxoviruses (measles virus, mumps virus, and Newcastle disease virus), nucleotide diversity at both non-coding sites and at nonsynonymous sites in coding regions was significantly reduced in comparison to that at synonymous sites. Likewise, both the mean and variance of gene diversity at nonsynonymous polymorphic sites were reduced in comparison to non-coding and synonymous sites. Neither of these patterns, which reflect the action of Purifying Selection against deleterious mutations at nonsynonymous and non-coding sites, were seen in the case of live attenuated vaccine strains, implying that Purifying Selection has been substantially relaxed on the latter, potentially affecting their biological properties, including antigenicity and vaccine effectiveness. Since the accumulation of mutations increases as a function of the number of generations of replication, these findings highlight the utility of minimizing the number of generations between the original vaccine master seed and the strains used in vaccination, along with periodic monitoring of the extent of sequence evolution.
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More effective Purifying Selection on RNA viruses than in DNA viruses.
Gene, 2007Co-Authors: Austin L. Hughes, Mary Ann K. HughesAbstract:Analysis of the pattern of nucleotide diversity in 222 independent viral sequence datasets showed the prevalence of Purifying Selection. In spite of the higher mutation rate of RNA viruses, our analyses revealed stronger evidence of the action of Purifying Selection in RNA viruses than in DNA viruses. The ratio of nonsynonymous to synonymous nucleotide diversity was significantly lower in RNA viruses than in DNA viruses, indicating that nonsynonymous mutations have been removed at a greater rate (relative to the mutation rate) in the former than in the latter. Moreover, statistics that measure the occurrence of rare polymorphisms revealed significantly a greater excess of rare nonsynonymous polymorphisms in RNA viruses than in DNA viruses but no difference with respect to synonymous polymorphisms. Since rare nonsynonymous polymorphisms are likely to be undergoing the effects of Purifying Selection acting to eliminate them, this result implies a stronger signature of ongoing Purifying Selection in RNA viruses than in DNA viruses. Across datasets from both DNA viruses and RNA viruses, we found a negatively allometric relationship between nonsynonymous and synonymous nucleotide diversity; in other words, nonsynonymous nucleotide diversity increased with synonymous nucleotide diversity at a less than linear rate. These findings are most easily explained by the occurrence of slightly deleterious mutations. The fact that the negative allometry was more pronounced in RNA viruses than in DNA viruses provided additional evidence that Purifying Selection is more effective in the former than in the latter.
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Micro-scale signature of Purifying Selection in Marburg virus genomes.
Gene, 2007Co-Authors: Austin L. HughesAbstract:In the seven protein-coding genes in the Marburg virus (MARV) genome, the synonymous nucleotide diversity substantially exceeded the nonsynonymous nucleotide diversity, indicating strong Purifying Selection. Likewise, there was evidence of Purifying Selection on 5'UTR and 3'UTR, where nucleotide diversity (pi) was significantly less than piS in the coding regions. Nonsynonymous polymorphic sites showed significantly reduced mean gene diversity in comparison to other polymorphic sites, indicating that Purifying Selection at certain slightly deleterious nonsynonymous polymorphisms is ongoing. Moreover, nonsynonymous polymorphic sites showed significantly reduced gene diversity in comparison to adjacent synonymous sites, even though the vast majority of such adjacent synonymous sites were in the same codon or an adjacent codon. Thus Purifying Selection, in conjunction with recombination and/or backward mutation, can act to break up linkage relationships at a micro-scale in the MARV genome. The ability of Purifying Selection to break up linkage between synonymous and nonsynonymous polymorphisms on such a fine scale has not been reported in any other genome.
Sam Yeaman - One of the best experts on this subject based on the ideXlab platform.
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Purifying Selection does not drive signatures of convergent local adaptation of lodgepole pine and interior spruce
BMC Evolutionary Biology, 2019Co-Authors: Mengmeng Lu, Kathryn A. Hodgins, Jon C. Degner, Sam YeamanAbstract:BackgroundLodgepole pine (Pinus contorta) and interior spruce (Picea glauca, Picea engelmannii, and their hybrids) are distantly related conifer species. Previous studies identified 47 genes containing variants associated with environmental variables in both species, providing evidence of convergent local adaptation. However, if the intensity of Purifying Selection varies with the environment, clines in nucleotide diversity could evolve through linked (background) Selection that would yield allele frequency-environment signatures resembling local adaptation. If similar geographic patterns in the strength of Purifying Selection occur in these species, this could result in the convergent signatures of local adaptation, especially if the landscape of recombination is conserved. In the present study, we investigated whether spatially/environmentally varying Purifying Selection could give rise to the convergent signatures of local adaptation that had previously reported.ResultsWe analyzed 86 lodgepole pine and 50 interior spruce natural populations spanning heterogeneous environments in western Canada where previous analyses had found signatures of convergent local adaptation. We estimated nucleotide diversity and Tajima’s D for each gene within each population and calculated the strength of correlations between nucleotide diversity and environmental variables. Overall, these estimates in the genes with previously identified convergent local adaptation signatures had no similar pattern between pine and spruce. Clines in nucleotide diversity along environmental variables were found for interior spruce, but not for lodgepole pine. In spruce, genes with convergent adaption signatures showed a higher strength of correlations than genes without convergent adaption signatures, but there was no such disparity in pine, which suggests the pattern in spruce may have arisen due to a combination of Selection and hybridization.ConclusionsThe results rule out Purifying/background Selection as a driver of convergent local adaption signatures in lodgepole pine and interior spruce.
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Purifying Selection does not drive signatures of convergent local adaptation of lodgepole pine and interior spruce.
BMC evolutionary biology, 2019Co-Authors: Kathryn A. Hodgins, Jon C. Degner, Sam YeamanAbstract:Lodgepole pine (Pinus contorta) and interior spruce (Picea glauca, Picea engelmannii, and their hybrids) are distantly related conifer species. Previous studies identified 47 genes containing variants associated with environmental variables in both species, providing evidence of convergent local adaptation. However, if the intensity of Purifying Selection varies with the environment, clines in nucleotide diversity could evolve through linked (background) Selection that would yield allele frequency-environment signatures resembling local adaptation. If similar geographic patterns in the strength of Purifying Selection occur in these species, this could result in the convergent signatures of local adaptation, especially if the landscape of recombination is conserved. In the present study, we investigated whether spatially/environmentally varying Purifying Selection could give rise to the convergent signatures of local adaptation that had previously reported. We analyzed 86 lodgepole pine and 50 interior spruce natural populations spanning heterogeneous environments in western Canada where previous analyses had found signatures of convergent local adaptation. We estimated nucleotide diversity and Tajima’s D for each gene within each population and calculated the strength of correlations between nucleotide diversity and environmental variables. Overall, these estimates in the genes with previously identified convergent local adaptation signatures had no similar pattern between pine and spruce. Clines in nucleotide diversity along environmental variables were found for interior spruce, but not for lodgepole pine. In spruce, genes with convergent adaption signatures showed a higher strength of correlations than genes without convergent adaption signatures, but there was no such disparity in pine, which suggests the pattern in spruce may have arisen due to a combination of Selection and hybridization. The results rule out Purifying/background Selection as a driver of convergent local adaption signatures in lodgepole pine and interior spruce.
Stephen I Wright - One of the best experts on this subject based on the ideXlab platform.
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association mapping reveals the role of Purifying Selection in the maintenance of genomic variation in gene expression
Proceedings of the National Academy of Sciences of the United States of America, 2015Co-Authors: Emily B Josephs, John R Stinchcombe, Stephen I WrightAbstract:The evolutionary forces that maintain genetic variation in quantitative traits within populations remain poorly understood. One hypothesis suggests that variation is under Purifying Selection, resulting in an excess of low-frequency variants and a negative correlation between minor allele frequency and Selection coefficients. Here, we test these predictions using the genetic loci associated with total expression variation (eQTLs) and allele-specific expression variation (aseQTLs) mapped within a single population of the plant Capsella grandiflora. In addition to finding eQTLs and aseQTLs for a large fraction of genes, we show that alleles at these loci are rarer than expected and exhibit a negative correlation between phenotypic effect size and frequency. Overall, our results show that the distribution of frequencies and effect sizes of the loci responsible for local expression variation within a single outcrossing population are consistent with the effects of Purifying Selection.
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pollen specific but not sperm specific genes show stronger Purifying Selection and higher rates of positive Selection than sporophytic genes in capsella grandiflora
Molecular Biology and Evolution, 2013Co-Authors: Ramesh Arunkumar, Emily B Josephs, Robert J Williamson, Stephen I WrightAbstract:Selection on the gametophyte can be a major force shaping plant genomes as 7–11% of genes are expressed only in that phase and 60% of genes are expressed in both the gametophytic and sporophytic phases. The efficacy of Selection on gametophytic tissues is likely to be influenced by sexual Selection acting on male and female functions of hermaphroditic plants. Moreover, the haploid nature of the gametophytic phase allows Selection to be efficient in removing recessive deleterious mutations and fixing recessive beneficial mutations. To assess the importance of gametophytic Selection, we compared the strength of Purifying Selection and extent of positive Selection on gametophyte- and sporophyte-specific genes in the highly outcrossing plant Capsella grandiflora. We found that pollen-exclusive genes had a larger fraction of sites under strong Purifying Selection, a greater proportion of adaptive substitutions, and faster protein evolution compared with seedling-exclusive genes. In contrast, sperm cell-exclusive genes had a smaller fraction of sites under strong Purifying Selection, a lower proportion of adaptive substitutions, and slower protein evolution compared with seedlingexclusive genes. Observations of strong Selection acting on pollen-expressed genes are likely explained by sexual Selection resulting from pollen competition aided by the haploid nature of that tissue. The relaxation of Selection in sperm might be due to the reduced influence of intrasexual competition, but reduced gene expression may also be playing an important role.
Michael M. Desai - One of the best experts on this subject based on the ideXlab platform.
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the effect of strong Purifying Selection on genetic diversity
bioRxiv, 2017Co-Authors: Ivana Cvijovic, Benjamin H Good, Michael M. DesaiAbstract:Purifying Selection reduces genetic diversity, both at sites under direct Selection and at linked neutral sites. This process, known as background Selection, is thought to play an important role in shaping genomic diversity in natural populations. Yet despite its importance, the effects of background Selection are not fully understood. Previous theoretical analyses of this process have taken a backwards-time approach based on the structured coalescent. While they provide some insight, these methods are either limited to very small samples or are computationally prohibitive. Here, we present a new forward-time analysis of the trajectories of both neutral and deleterious mutations at a nonrecombining locus. We find that strong Purifying Selection leads to remarkably rich dynamics: neutral mutations can exhibit sweep-like behavior, and deleterious mutations can reach substantial frequencies even when they are guaranteed to eventually go extinct. Our analysis of these dynamics allows us to calculate analytical expressions for the full site frequency spectrum. We find that whenever background Selection is strong enough to lead to a reduction in genetic diversity, it also results in substantial distortions to the site frequency spectrum, which can mimic the effects of population expansions or positive Selection. Because these distortions are most pronounced in the low and high frequency ends of the spectrum, they become particularly important in larger samples, but may have small effects in smaller samples. We also apply our forward-time framework to calculate other quantities, such as the ultimate fates of polymorphisms or the fitnesses of their ancestral backgrounds.
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Distortions in Genealogies due to Purifying Selection and Recombination
Genetics, 2013Co-Authors: Lauren E. Nicolaisen, Michael M. DesaiAbstract:Purifying Selection at many linked sites alters patterns of molecular evolution, reducing overall diversity and distorting the shapes of genealogies. Recombination attenuates these effects; however, Purifying Selection can significantly distort genealogies even for substantial recombination rates. Here, we show that when Selection and/or recombination are sufficiently strong, the genealogy at any single site can be described by a time-dependent effective population size, Ne(t), which has a simple analytic form. Our results illustrate how recombination reduces distortions in genealogies and allow us to quantitatively describe the shapes of genealogies in the presence of strong Purifying Selection and recombination. We also analyze the effects of a distribution of Selection coefficients across the genome.
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The equivalence between weak and strong Purifying Selection
arXiv: Populations and Evolution, 2012Co-Authors: Benjamin H Good, Michael M. DesaiAbstract:Weak Purifying Selection, acting on many linked mutations, may play a major role in shaping patterns of molecular evolution in natural populations. Yet efforts to infer these effects from DNA sequence data are limited by our incomplete understanding of weak Selection on local genomic scales. Here, we demonstrate a natural symmetry between weak and strong Selection, in which the effects of many weakly selected mutations on patterns of molecular evolution are equivalent to a smaller number of more strongly selected mutations. By introducing a coarse-grained "effective Selection coefficient," we derive an explicit mapping between weakly selected populations and their strongly selected counterparts, which allows us to make accurate and efficient predictions across the full range of Selection strengths. This suggests that an effective Selection coefficient and effective mutation rate --- not an effective population size --- is the most accurate summary of the effects of Selection over locally linked regions. Moreover, this correspondence places fundamental limits on our ability to resolve the effects of weak Selection from contemporary sequence data alone.
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Distortions in Genealogies Due to Purifying Selection
Molecular biology and evolution, 2012Co-Authors: Lauren E. Nicolaisen, Michael M. DesaiAbstract:Purifying Selection can substantially alter patterns of molecular evolution. Its main effect is to reduce overall levels of genetic variation, leading to a reduced effective population size. However, it also distorts genealogies relative to neutral expectations. A structured coalescent method has been used to describe this effect, and forms the basis for numerical methods and simulations. In this study, we extend this approach by making the additional approximation that lineages may be treated independently, which is valid only in the strong Selection regime. We show that in this regime, the distortions due to Purifying Selection can be described by a time-dependent effective population size and mutation rate, confirming earlier intuition. We calculate simple analytical expressions for these functions, N(e)(t) and U(e)(t). These results allow us to describe the structure of genealogies in a population under strong Purifying Selection as equivalent to a purely neutral population with varying population size and mutation rate, thereby enabling the use of neutral methods of inference and estimation for populations in the strong Selection regime.
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Research article Distortions in Genealogies Due to Purifying Selection
2012Co-Authors: Lauren E. Nicolaisen, Michael M. DesaiAbstract:Purifying Selection can substantially alter patterns of molecular evolution. Its main effect is to reduce overall levels of genetic variation, leading to a reduced effective population size. However, it also distorts genealogies relative to neutral expectations. A structured coalescent method has been used to describe this effect, and forms the basis for numerical methods and simulations. In this study, we extend this approach by making the additional approximation that lineages may be treated independently, which is valid only in the strong Selection regime. We show that in this regime, the distortions due to Purifying Selection can be described by a time-dependent effective population size and mutation rate, confirming earlier intuition. We calculate simple analytical expressions for these functions, Ne(t )a ndUe(t). These results allow us to describe the structure of genealogies in a population under strong Purifying Selection as equivalent to a purely neutral population with varying population size and mutation rate, thereby enabling the use of neutral methods of inference and estimation for populations in the strong Selection regime.
Dmitri A. Petrov - One of the best experts on this subject based on the ideXlab platform.
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strong Purifying Selection on codon usage bias
bioRxiv, 2017Co-Authors: Heather E Machado, David S Lawrie, Dmitri A. PetrovAbstract:Codon usage bias (CUB), where certain codons are used more frequently than expected by chance, is a ubiquitous phenomenon and occurs across the tree of life. The dominant paradigm is that the proportion of preferred codons is set by weak Selection. Though experimental changes in codon usage have shown large phenotypic effects, genome-wide population genetics estimates have generally been consistent with the weak Selection model. Here we use site frequency spectrum and polymorphism- level data from deep Drosophila melanogaster population genomic sequencing to measure Selection on synonymous sites. We find evidence that Purifying Selection on preferred codons varies in strength from weak to strong (Nes < −10). Our results suggest a new model where the level of CUB in a gene is determined by distribution of Selection coefficients across sites. These results also indicate that the functional effect of CUB, and of synonymous sites in general, have been underestimated.
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Strong Purifying Selection at Synonymous Sites in D. melanogaster
PLoS genetics, 2013Co-Authors: David S Lawrie, Philipp W. Messer, Ruth Hershberg, Dmitri A. PetrovAbstract:Synonymous sites are generally assumed to be subject to weak selective constraint. For this reason, they are often neglected as a possible source of important functional variation. We use site frequency spectra from deep population sequencing data to show that, contrary to this expectation, 22% of four-fold synonymous (4D) sites in Drosophila melanogaster evolve under very strong selective constraint while few, if any, appear to be under weak constraint. Linking polymorphism with divergence data, we further find that the fraction of synonymous sites exposed to strong Purifying Selection is higher for those positions that show slower evolution on the Drosophila phylogeny. The function underlying the inferred strong constraint appears to be separate from splicing enhancers, nucleosome positioning, and the translational optimization generating canonical codon bias. The fraction of synonymous sites under strong constraint within a gene correlates well with gene expression, particularly in the mid-late embryo, pupae, and adult developmental stages. Genes enriched in strongly constrained synonymous sites tend to be particularly functionally important and are often involved in key developmental pathways. Given that the observed widespread constraint acting on synonymous sites is likely not limited to Drosophila, the role of synonymous sites in genetic disease and adaptation should be reevaluated.
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Relaxed Purifying Selection and Possibly High Rate of Adaptation in Primate Lineage-Specific Genes
Genome biology and evolution, 2010Co-Authors: James J. Cai, Dmitri A. PetrovAbstract:Genes in the same organism vary in the time since their evolutionary origin. Without horizontal gene transfer, young genes are necessarily restricted to a few closely related species, whereas old genes can be broadly distributed across the phylogeny. It has been shown that young genes evolve faster than old genes; however, the evolutionary forces responsible for this pattern remain obscure. Here, we classify human-chimp protein-coding genes into different age classes, according to the breath of their phylogenetic distribution. We estimate the strength of Purifying Selection and the rate of adaptive Selection for genes in different age classes. We find that older genes carry fewer and less frequent nonsynonymous single-nucleotide polymorphisms than younger genes suggesting that older genes experience a stronger Purifying Selection at the protein-coding level. We infer the distribution of fitness effects of new deleterious mutations and find that older genes have proportionally more slightly deleterious mutations and fewer nearly neutral mutations than younger genes. To investigate the role of adaptive Selection of genes in different age classes, we determine the Selection coefficient (gamma = 2N(e)s) of genes using the MKPRF approach and estimate the ratio of the rate of adaptive nonsynonymous substitution to synonymous substitution (omega(A)) using the DoFE method. Although the proportion of positively selected genes (gamma > 0) is significantly higher in younger genes, we find no correlation between omega(A) and gene age. Collectively, these results provide strong evidence that younger genes are subject to weaker Purifying Selection and more tenuous evidence that they also undergo adaptive evolution more frequently.
