Impact of demography on linked selection in two outcrossing Brassicaceae species.
ABSTRACT: Genetic diversity is shaped by mutation, genetic drift, gene flow, recombination, and selection. The dynamics and interactions of these forces shape genetic diversity across different parts of the genome, between populations and species. Here, we have studied the effects of linked selection on nucleotide diversity in outcrossing populations of two Brassicaceae species, Arabidopsis lyrata and Capsella grandiflora, with contrasting demographic history. In agreement with previous estimates, we found evidence for a modest population size expansion thousands of generations ago, as well as efficient purifying selection in C. grandiflora. In contrast, the A. lyrata population exhibited evidence for very recent strong population size decline and weaker efficacy of purifying selection. Using multiple regression analyses with recombination rate and other genomic covariates as explanatory variables, we can explain 47% of the variance in neutral diversity in the C. grandiflora population, while in the A. lyrata population, only 11% of the variance was explained by the model. Recombination rate had a significant positive effect on neutral diversity in both species, suggesting that selection at linked sites has an effect on patterns of neutral variation. In line with this finding, we also found reduced neutral diversity in the vicinity of genes in the C. grandiflora population. However, in A. lyrata no such reduction in diversity was evident, a finding that is consistent with expectations of the impact of a recent bottleneck on patterns of neutral diversity near genes. This study thus empirically demonstrates how differences in demographic history modulate the impact of selection at linked sites in natural populations.
Project description:Studies of nucleotide diversity have found an excess of low-frequency amino acid polymorphisms segregating in Arabidopsis thaliana, suggesting a predominance of weak purifying selection acting on amino acid polymorphism in this inbreeding species. Here, we investigate levels of diversity and divergence at synonymous and nonsynonymous sites in 6 circumpolar populations of the outbreeding Arabidopsis lyrata and compare these results with A. thaliana, to test for differences in mutation and selection parameters across genes, populations, and species. We find that A. lyrata shows an excess of low-frequency nonsynonymous polymorphisms both within populations and species wide, consistent with weak purifying selection similar to the patterns observed in A. thaliana. Furthermore, nonsynonymous polymorphisms tend to be more restricted in their population distribution in A. lyrata, consistent with purifying selection preventing their geographic spread. Highly expressed genes show a reduced ratio of amino acid to synonymous change for both polymorphism and fixed differences, suggesting a general pattern of stronger purifying selection on high-expression proteins.
Project description:BACKGROUND:Examining allelic variation of R-genes in closely related perennial species of Arabidopsis thaliana is critical to understanding how population structure and ecology interact with selection to shape the evolution of innate immunity in plants. We finely sampled natural populations of Arabidopsis lyrata from the Great Lakes region of North America (A. l. lyrata) and broadly sampled six European countries (A. l. petraea) to investigate allelic variation of two R-genes (RPM1 and WRR4) and neutral genetic markers (Restriction Associated DNA sequences and microsatellites) in relation to mating system, phylogeographic structure and subspecies divergence. RESULTS:Fine-scale sampling of populations revealed strong effects of mating system and population structure on patterns of polymorphism for both neutral loci and R-genes, with no strong evidence for selection. Broad geographic sampling revealed evidence of balancing selection maintaining polymorphism in R-genes, with elevated heterozygosity and diversity compared to neutral expectations and sharing of alleles among diverged subspecies. Codon-based tests detected both positive and purifying selection for both R-genes, as commonly found for animal immune genes. CONCLUSIONS:Our results highlight that combining fine and broad-scale sampling strategies can reveal the multiple factors influencing polymorphism and divergence at potentially adaptive genes such as R-genes.
Project description:Genetic diversity is unusually high at loci in the S-locus region of the self-incompatible species of the flowering plant, Arabidopsis lyrata, not just in the S loci themselves, but also at two nearby loci. In a previous study of a single natural population from Iceland, we attributed this elevated polymorphism to linkage disequilibrium (LD) between variants at loci close to the S locus and the S alleles, which are maintained in the population by balancing selection. With the four S-flanking loci whose diversity we previously studied, we could not determine the extent of the region linked to the S loci in which neutral sites are affected. We also could not exclude the possibility of a population bottleneck, or of admixture, as causes of the LD. We have now studied four more distant loci flanking the S-locus region, and more populations, and we analyze the results using a theoretical model of the effect of balancing selection on diversity at linked neutral sites within and between different functional S-allelic classes. In the model, diversity is a function of the number of selectively maintained alleles and the recombination distances from the selectively maintained sites. We use the model to estimate the number of different functional S alleles, their turnover rate, and recombination rates between the S-locus region and other loci. Our estimates suggest that there is a small region of very low recombination surrounding the S-locus region.
Project description:X and Y chromosomes differ in effective population size (Ne ), rates of recombination, and exposure to natural selection, all of which can affect patterns of genetic diversity. On Y chromosomes with suppressed recombination, natural selection is expected to eliminate linked neutral variation, and lower the Ne of Y compared to X chromosomes or autosomes. However, female-biased sex ratios and high variance in male reproductive success can also reduce Y-linked Ne , making it difficult to infer the causes of low Y-diversity. Here, we investigate the factors affecting levels of polymorphism during sex chromosome evolution in the dioecious plant Rumexhastatulus (Polygonaceae). Strikingly, we find that neutral diversity for genes on the Y chromosome is, on average, 2.1% of the value for their X-linked homologs, corresponding to a chromosome-wide reduction of 93% compared to the standard neutral expectation. We demonstrate that the magnitude of this diversity loss is inconsistent with reduced male Ne caused by neutral processes. Instead, using forward simulations and estimates of the distribution of deleterious fitness effects, we show that Y chromosome diversity loss can be explained by purifying selection acting in aggregate over a large number of genetically linked sites. Simulations also suggest that our observed level of Y-diversity is consistent with the joint action of purifying and positive selection, but only for models in which there were fewer constrained sites than we empirically estimated. Given the relatively recent origin of R. hastatulus sex chromosomes, our results imply that Y-chromosome degeneration in the early stages may be largely driven by selective interference rather than by neutral genetic drift of silenced Y-linked genes.
Project description:It is well known that most new mutations that affect fitness exert deleterious effects and that natural populations are often composed of subpopulations (demes) connected by gene flow. To gain a better understanding of the joint effects of purifying selection and population structure, we focus on a scenario where an ancestral population splits into multiple demes and study neutral diversity patterns in regions linked to selected sites. In the background selection regime of strong selection, we first derive analytic equations for pairwise coalescent times and FST as a function of time after the ancestral population splits into two demes and then construct a flexible coalescent simulator that can generate samples under complex models such as those involving multiple demes or nonconservative migration. We have carried out extensive forward simulations to show that the new methods can accurately predict diversity patterns both in the nonequilibrium phase following the split of the ancestral population and in the equilibrium between mutation, migration, drift, and selection. In the interference selection regime of many tightly linked selected sites, forward simulations provide evidence that neutral diversity patterns obtained from both the nonequilibrium and equilibrium phases may be virtually indistinguishable for models that have identical variance in fitness, but are nonetheless different with respect to the number of selected sites and the strength of purifying selection. This equivalence in neutral diversity patterns suggests that data collected from subdivided populations may have limited power for differentiating among the selective pressures to which closely linked selected sites are subject.
Project description:We investigated DNA sequence diversity for loci on chromosomes 1 and 2 in six natural populations of Arabidopsis lyrata and tested for the role of natural selection in structuring genomewide patterns of variability, specifically examining the effects of recombination rate on levels of silent polymorphism. In contrast with theoretical predictions from models of genetic hitchhiking, maximum-likelihood-based analyses of diversity and divergence do not suggest reduction of diversity in the region of suppressed recombination near the centromere of chromosome 1, except in a single population from Russia, in which the pericentromeric region may have undergone a local selective sweep or demographic process that reduced variability. We discuss various possibilities that might explain why nucleotide diversity in most A. lyrata populations is not related to recombination rate, including genic recombination hotspots, and low gene density in the low recombination rate region.
Project description:A correlation between diversity levels and rates of recombination is predicted both by models of positive selection, such as hitchhiking associated with the rapid fixation of advantageous mutations, and by models of purifying selection against strongly deleterious mutations (commonly referred to as "background selection"). With parameter values appropriate for Drosophila populations, only the first class of models predicts a marked skew in the frequency spectrum of linked neutral variants, relative to a neutral model. Here, we consider 29 loci scattered throughout the Drosophila melanogaster genome. We show that, in African populations, a summary of the frequency spectrum of polymorphic mutations is positively correlated with the meiotic rate of crossing over. This pattern is demonstrated to be unlikely under a model of background selection. Models of weakly deleterious selection are not expected to produce both the observed correlation and the extent to which nucleotide diversity is reduced in regions of low (but nonzero) recombination. Thus, of existing models, hitchhiking due to the recurrent fixation of advantageous variants is the most plausible explanation for the data.
Project description:Positive selection and purifying selection reduce levels of variation at linked neutral loci. One consequence of these processes is that the amount of neutral diversity and the meiotic recombination rate are predicted to be positively correlated across the genome-a prediction met in some species but not others. To better document the prevalence of selection at linked sites, we used new and published whole-genome sequences to survey nucleotide variation in population samples of the western European house mouse (Mus musculus domesticus) from Germany, France, and Gough Island, a remote volcanic island in the south Atlantic. Correlations between sequence variation and recombination rates estimated independently from dense linkage maps were consistently very weak (????0.06), though they exceeded conventional significance thresholds. This pattern persisted in comparisons between genomic regions with the highest and lowest recombination rates, as well as in models incorporating the density of transcribed sites, the density of CpG dinucleotides, and divergence between mouse and rat as covariates. We conclude that natural selection affects linked neutral variation in a restricted manner in the western European house mouse.
Project description:A major goal in evolutionary biology is to understand how natural selection has shaped patterns of genetic variation across genomes. Studies in a variety of species have shown that neutral genetic diversity (intra-species differences) has been reduced at sites linked to those under direct selection. However, the effect of linked selection on neutral sequence divergence (inter-species differences) remains ambiguous. While empirical studies have reported correlations between divergence and recombination, which is interpreted as evidence for natural selection reducing linked neutral divergence, theory argues otherwise, especially for species that have diverged long ago. Here we address these outstanding issues by examining whether natural selection can affect divergence between both closely and distantly related species. We show that neutral divergence between closely related species (e.g. human-primate) is negatively correlated with functional content and positively correlated with human recombination rate. We also find that neutral divergence between distantly related species (e.g. human-rodent) is negatively correlated with functional content and positively correlated with estimates of background selection from primates. These patterns persist after accounting for the confounding factors of hypermutable CpG sites, GC content, and biased gene conversion. Coalescent models indicate that even when the contribution of ancestral polymorphism to divergence is small, background selection in the ancestral population can still explain a large proportion of the variance in divergence across the genome, generating the observed correlations. Our findings reveal that, contrary to previous intuition, natural selection can indirectly affect linked neutral divergence between both closely and distantly related species. Though we cannot formally exclude the possibility that the direct effects of purifying selection drive some of these patterns, such a scenario would be possible only if more of the genome is under purifying selection than currently believed. Our work has implications for understanding the evolution of genomes and interpreting patterns of genetic variation.
Project description:The human Y chromosome exhibits surprisingly low levels of genetic diversity. This could result from neutral processes if the effective population size of males is reduced relative to females due to a higher variance in the number of offspring from males than from females. Alternatively, selection acting on new mutations, and affecting linked neutral sites, could reduce variability on the Y chromosome. Here, using genome-wide analyses of X, Y, autosomal and mitochondrial DNA, in combination with extensive population genetic simulations, we show that low observed Y chromosome variability is not consistent with a purely neutral model. Instead, we show that models of purifying selection are consistent with observed Y diversity. Further, the number of sites estimated to be under purifying selection greatly exceeds the number of Y-linked coding sites, suggesting the importance of the highly repetitive ampliconic regions. While we show that purifying selection removing deleterious mutations can explain the low diversity on the Y chromosome, we cannot exclude the possibility that positive selection acting on beneficial mutations could have also reduced diversity in linked neutral regions, and may have contributed to lowering human Y chromosome diversity. Because the functional significance of the ampliconic regions is poorly understood, our findings should motivate future research in this area.