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Bret A Payseur

Publications and source records attributed to Bret A Payseur.

12 recordsLinked to original sources
PubMed2007

Searching the genomes of inbred mouse strains for incompatibilities that reproductively isolate their wild relatives.

Identification of the genes that underlie reproductive isolation provides important insights into the process of speciation. According to the Dobzhansky-Muller model, these genes suffer disrupted interactions in hybrids due to independent divergence in separate populations. In hybrid populations, natural selection acts to remove the deleterious heterospecific combinations that cause these functional disruptions. When selection is strong, this process can maintain multilocus associations, primarily between conspecific alleles, providing a signature that can be used to locate incompatibilities. We applied this logic to populations of house mice that were formed by hybridization involving two species that show partial reproductive isolation, Mus domesticus and Mus musculus. Using molecular markers likely to be informative about species ancestry, we scanned the genomes of 1) classical inbred strains and 2) recombinant inbred lines for pairs of loci that showed extreme linkage disequilibria. By using the same set of markers, we identified a list of locus pairs that displayed similar patterns in both scans. These genomic regions may contain genes that contribute to reproductive isolation between M. domesticus and M. musculus. This hypothesis can now be tested using laboratory crosses and surveys of introgression in the wild.

Animals↗
PubMed2006

Integrating patterns of polymorphism at SNPs and STRs.

Single nucleotide polymorphisms (SNPs) and short tandem repeats (STRs) differ in mutation rate and mechanism. As a result of these differences, simultaneous consideration of polymorphism patterns at SNPs and STRs can provide insights that are difficult to obtain from analysis of either marker type in isolation. Here, we use coalescent simulations to model the opposing effects of contrasting mutational dynamics and of shared genealogical history on the correlation between polymorphism at linked SNPs and STRs. Results show that polymorphism patterns are correlated only weakly despite the shared underlying genealogy, underscoring the importance of divergent mutational processes. Examples illustrate how knowledge of these relationships could aid population genetic inference, indicating the need for thorough theoretical studies.

Animals↗
PubMed2006

Contrasting multi-site genotypic distributions among discordant quantitative phenotypes: the APOA1/C3/A4/A5 gene cluster and cardiovascular disease risk factors.

Most tests of association between DNA sequence variation and quantitative phenotypes in samples of randomly chosen individuals rely on specification of genotypic strata followed by comparison of phenotypes across these strata. This strategy often succeeds when phenotypic differences are caused by one or two single nucleotide polymorphisms (SNPs) among the surveyed markers. However, when multiple-SNP haplotypes account for observed phenotypic variation, identification of the best partitioning requires examination of an inordinate number of SNP combinations. An alternative approach is to rank individuals by their phenotypic measures and ask whether attributes of the genotypic variation show a non-random distribution along this phenotypic ranking. One simple version of this strategy selects the top and bottom tails of the distribution, and then tests whether genotypes from these two samples are drawn from a single population. This framework does not require the recovery of phased haplotypes and allows contrasts between large numbers of sites at once. We use a method based on this approach to identify associations between plasma triglyceride level, a risk factor for cardiovascular disease, and multi-site genotypes located in the APOA1/C3/A4/A5 cluster of apolipoprotein genes in unrelated individuals (1,071 African-American females, 780 African-American males, 1,036 European-American females, and 930 European-American males) sampled from four US cities as part of the Coronary Artery Risk Development in Young Adults (CARDIA) study. Method performance is investigated using simulations that model genealogical variation and different genetic architectures. Results indicate that this multi-site test can identify genotype-phenotype associations with reasonable power, including those generated by some simple epistatic models.

Adult↗
PubMed2005

Signatures of reproductive isolation in patterns of single nucleotide diversity across inbred strains of mice.

Reproductive isolation is often caused by the disruption of genic interactions that evolve in geographically separate populations. Identifying the genomic regions and genes involved in these interactions, known as "Dobzhansky-Muller incompatibilities," can be challenging but is facilitated by the wealth of genetic markers now available in model systems. In recent years, the complete genome sequence and thousands of single nucleotide polymorphisms (SNPs) from laboratory mice, which are largely genetic hybrids between Mus musculus and M. domesticus, have become available. Here, we use these resources to locate genomic regions that may underlie reproductive isolation between these two species. Using genotypes from 332 SNPs that differ between wild-derived strains of M. musculus and M. domesticus, we identified several physically unlinked SNP pairs that show exceptional gametic disequilibrium across the lab strains. Conspecific alleles were associated in a disproportionate number of these cases, consistent with the action of natural selection against hybrid gene combinations. As predicted by the Dobzhansky-Muller model, this bias was differentially attributable to locus pairs for which one hybrid genotype was missing. We assembled a list of potential Dobzhansky-Muller incompatibilities from locus pairs that showed extreme associations (only three gametic types) among conspecific alleles. Two SNPs in this list map near known hybrid sterility loci on chromosome 17 and the X chromosome, allowing us to nominate partners for disrupted interactions involving these genomic regions for the first time. Together, these results indicate that patterns produced by speciation between M. musculus and M. domesticus are visible in the genomes of lab strains of mice, underscoring the potential of these genetic model organisms for addressing general questions in evolutionary biology.

Animals↗
PubMed2004

Genome scans of DNA variability in humans reveal evidence for selective sweeps outside of Africa.

The last 50,000-150,000 years of human history have been characterized by rapid demographic expansions and the colonization of novel environments outside of sub-Saharan Africa. Mass migrations outside the ancestral species range likely entailed many new selection pressures, suggesting that genetic adaptation to local environmental conditions may have been more prevalent in colonizing populations outside of sub-Saharan Africa. Here we report a test of this hypothesis using genome-wide patterns of DNA polymorphism. We conducted a multilocus scan of microsatellite variability to identify regions of the human genome that may have been subject to continent-specific hitchhiking events. Using published polymorphism data for a total of 624 autosomal loci in multiple populations of humans, we used coalescent simulations to identify candidate loci for geographically restricted selective sweeps. We identified a total of 13 loci that appeared as outliers in replicated population comparisons involving different reference samples for Africa. A disproportionate number of these loci exhibited reduced levels of relative variability in non-African populations alone, suggesting that recent episodes of positive selection have been more prevalent outside of sub-Saharan Africa.

Africa↗
PubMed2004

Comparative recombination rates in the rat, mouse, and human genomes.

Levels of recombination vary among species, among chromosomes within species, and among regions within chromosomes in mammals. This heterogeneity may affect levels of diversity, efficiency of selection, and genome composition, as well as have practical consequences for the genetic mapping of traits. We compared the genetic maps to the genome sequence assemblies of rat, mouse, and human to estimate local recombination rates across these genomes. Humans have greater overall levels of recombination, as well as greater variance. In rat and mouse, the size of the chromosome and proximity to telomere have less effect on local recombination rate than in human. At the chromosome level, rat and mouse X chromosomes have the lowest recombination rates, whereas human chromosome X does not show the same pattern. In all species, local recombination rate is significantly correlated with several sequence variables, including GC%, CpG density, repetitive elements, and the neutral mutation rate, with some pronounced differences between species. Recombination rate in one species is not strongly correlated with the rate in another, when comparing homologous syntenic blocks of the genome. This comparative approach provides additional insight into the causes and consequences of genomic heterogeneity in recombination.

Animals↗
PubMed2004

Differential patterns of introgression across the X chromosome in a hybrid zone between two species of house mice.

A complete understanding of the speciation process requires the identification of genomic regions and genes that confer reproductive barriers between species. Empirical and theoretical research has revealed two important patterns in the evolution of reproductive isolation in animals: isolation typically arises as a result of disrupted epistatic interactions between multiple loci and these disruptions map disproportionately to the X chromosome. These patterns suggest that a targeted examination of natural gene flow between closely related species at X-linked markers with known positions would provide insight into the genetic basis of speciation. We take advantage of the existence of genomic data and a well-documented European zone of hybridization between two species of house mice, Mus domesticus and M. musculus, to conduct such a survey. We evaluate patterns of introgression across the hybrid zone for 13 diagnostic X-linked loci with known chromosomal positions using a maximum likelihood model. Interlocus comparisons clearly identify one locus with reduced introgression across the center of the hybrid zone, pinpointing a candidate region for reproductive isolation. Results also reveal one locus with high frequencies of M. domesticus alleles in populations on the M. musculus side of the zone, suggesting the possibility that positive selection may act to drive the spread of alleles from one species on to the genomic background of the other species. Finally, cline width and cline center are strongly positively correlated across the X chromosome, indicating that gene flow of the X chromosome may be asymmetrical. This study highlights the utility of natural populations of hybrids for mapping speciation genes and suggests that the middle of the X chromosome may be important for reproductive isolation between species of house mice.

Animals↗
PubMed2003

Selection at linked sites in the partial selfer Caenorhabditis elegans.

Natural selection can produce a correlation between local recombination rates and levels of neutral DNA polymorphism as a consequence of genetic hitchhiking and background selection. Theory suggests that selection at linked sites should affect patterns of neutral variation in partially selfing populations more dramatically than in outcrossing populations. However, empirical investigations of selection at linked sites have focused primarily on outcrossing species. To assess the potential role of selection as a determinant of neutral polymorphism in the context of partial self-fertilization, we conducted a multivariate analysis of single-nucleotide polymorphism (SNP) density throughout the genome of the nematode Caenorhabditis elegans. We based the analysis on a published SNP data set and partitioned the genome into windows to calculate SNP densities, recombination rates, and gene densities across all six chromosomes. Our analyses identify a strong, positive correlation between recombination rate and neutral polymorphism (as estimated by noncoding SNP density) across the genome of C. elegans. Furthermore, we find that levels of neutral polymorphism are lower in gene-dense regions than in gene-poor regions in some analyses. Analyses incorporating local estimates of divergence between C. elegans and C. briggsae indicate that a mutational explanation alone is unlikely to explain the observed patterns. Consequently, we interpret these findings as evidence that natural selection shapes genome-wide patterns of neutral polymorphism in C. elegans. Our study provides the first demonstration of such an effect in a partially selfing animal. Explicit models of genetic hitchhiking and background selection can each adequately describe the relationship between recombination rate and SNP density, but only when they incorporate selfing rate. Clarification of the relative roles of genetic hitchhiking and background selection in C. elegans awaits the development of specific theoretical predictions that account for partial self-fertilization and biased sex ratios.

Animals↗
PubMed2003

Molecular correlates of genes exhibiting RNAi phenotypes in Caenorhabditis elegans.

Understanding genome-wide links between genotype and phenotype has generally been difficult due to both the complexity of phenotypes, and until recently, inaccessibility to large numbers of genes that might underlie a trait. To address this issue, we establish the association between particular RNAi phenotypes in Caenorhabditis elegans and sequence characteristics of the corresponding proteins and DNA. We find that genes showing RNAi phenotypes are long and highly expressed with little noncoding DNA and high rates of synonymous site substitution (KS). In addition, genes conferring RNAi phenotypes have significantly lower rates of nonsynonymous site substitution (KA). Collectively, these sequence features explain nearly 20% of the difference between the sets of loci that display or lack a RNAi-mediated effect, and reflect aspects both of the RNAi mechanism and the biological function of the genes. For example, the particularly low rate of evolution of genes in the sterility RNAi phenotype class suggests a role of C. elegans life history in shaping these patterns of sequence and expression characteristics on phenotypes. This approach also allows prediction of a set of heretofore-uncharacterized loci for which we expect future RNAi studies to reveal phenotypic effects (i.e., false negatives in present screens).

Animals↗
PubMed2002

Natural selection at linked sites in humans.

Theoretical and empirical work indicates that patterns of neutral polymorphism can be affected by linked, selected mutations. Under background selection, deleterious mutations removed from a population by purifying selection cause a reduction in linked neutral diversity. Under genetic hitchhiking, the rise in frequency and fixation of beneficial mutations also reduces the level of linked neutral polymorphism. Here we review the evidence that levels of neutral polymorphism in humans are affected by selection at linked sites. We then discuss four approaches for distinguishing between background selection and genetic hitchhiking based on (i) the relationship between polymorphism level and recombination rate for neutral loci with high mutation rates, (ii) relative levels of variation on the X chromosome and the autosomes, (iii) the frequency distribution of neutral polymorphisms, and (iv) population-specific patterns of genetic variation. Although the evidence for selection at linked sites in humans is clear, current methods and data do not allow us to clearly assess the relative importance of background selection and genetic hitchhiking in humans. These results contrast with those obtained for Drosophila, where the signals of positive selection are stronger.

Africa↗
PubMed2002

Searching for evidence of positive selection in the human genome using patterns of microsatellite variability.

Both natural selection and nonequilibrium population-level processes can lead to a skew in the frequency distribution of polymorphisms. Population-level processes are expected to affect all loci in a roughly equal fashion, whereas selection will affect only some regions of the genome. We conducted a sliding-window analysis of the frequency distribution of microsatellite polymorphisms across the human genome to identify regions that may be under positive selection. The analysis was based on a published data set of 5,257 mapped microsatellites in individuals of European ancestry. Observed and expected numbers of alleles were compared under a stepwise mutation model (SMM) using analytical formulae. Observed and expected heterozygosities were compared under a SMM using coalescent simulations. The two sets of analyses gave similar results. Approximately one-fourth of all loci showed a significant deficit of heterozygosity, consistent with a recent population expansion. Forty-three windows were identified with extreme skews in the frequency distribution of polymorphisms (in the direction of a deficit of heterozygosity, given the number of alleles). If these extreme windows are tracking selection at linked sites, theory predicts that they should be more common in regions of the genome with less recombination. We tested this prediction by comparing recombination rates in these extreme windows and in other regions of the genome and found that extreme windows had a significantly lower recombination rate than the genomic average. The proportion of extreme windows was significantly higher on the X chromosome than on the autosomes. Moreover, all the windows with extreme skews on the X chromosome were found in two clusters near the centromere; both these clusters exhibit markedly reduced recombination rates. These analyses point to regions of the genome that may recently have been subject to positive selection. These results also suggest that the effects of positive selection may be more pronounced on the X chromosome than on the autosomes in humans.

Alleles↗