A Genomic Map of the Effects of Linked Selection in Drosophila.

Natural selection at one site shapes patterns of genetic variation at linked sites. Quantifying the effects of "linked selection" on levels of genetic diversity is key to making reliable inference about demography, building a null model in scans for targets of adaptation, and learning about the dynamics of natural selection. Here, we introduce the first method that jointly infers parameters of distinct modes of linked selection, notably background selection and selective sweeps, from genome-wide diversity data, functional annotations and genetic maps. The central idea is to calculate the probability that a neutral site is polymorphic given local annotations, substitution patterns, and recombination rates. Information is then combined across sites and samples using composite likelihood in order to estimate genome-wide parameters of distinct modes of selection. In addition to parameter estimation, this approach yields a map of the expected neutral diversity levels along the genome. To illustrate the utility of our approach, we apply it to genome-wide resequencing data from 125 lines in Drosophila melanogaster and reliably predict diversity levels at the 1Mb scale. Our results corroborate estimates of a high fraction of beneficial substitutions in proteins and untranslated regions (UTR). They allow us to distinguish between the contribution of sweeps and other modes of selection around amino acid substitutions and to uncover evidence for pervasive sweeps in untranslated regions (UTRs). Our inference further suggests a substantial effect of other modes of linked selection and of adaptation in particular. More generally, we demonstrate that linked selection has had a larger effect in reducing diversity levels and increasing their variance in D. melanogaster than previously appreciated.

Pervasive adaptive protein evolution apparent in diversity patterns around amino acid substitutions in Drosophila simulans.

In Drosophila, multiple lines of evidence converge in suggesting that beneficial substitutions to the genome may be common. All suffer from confounding factors, however, such that the interpretation of the evidence-in particular, conclusions about the rate and strength of beneficial substitutions-remains tentative. Here, we use genome-wide polymorphism data in D. simulans and sequenced genomes of its close relatives to construct a readily interpretable characterization of the effects of positive selection: the shape of average neutral diversity around amino acid substitutions. As expected under recurrent selective sweeps, we find a trough in diversity levels around amino acid but not around synonymous substitutions, a distinctive pattern that is not expected under alternative models. This characterization is richer than previous approaches, which relied on limited summaries of the data (e.g., the slope of a scatter plot), and relates to underlying selection parameters in a straightforward way, allowing us to make more reliable inferences about the prevalence and strength of adaptation. Specifically, we develop a coalescent-based model for the shape of the entire curve and use it to infer adaptive parameters by maximum likelihood. Our inference suggests that ∼13% of amino acid substitutions cause selective sweeps. Interestingly, it reveals two classes of beneficial fixations: a minority (approximately 3%) that appears to have had large selective effects and accounts for most of the reduction in diversity, and the remaining 10%, which seem to have had very weak selective effects. These estimates therefore help to reconcile the apparent conflict among previously published estimates of the strength of selection. More generally, our findings provide unequivocal evidence for strongly beneficial substitutions in Drosophila and illustrate how the rapidly accumulating genome-wide data can be leveraged to address enduring questions about the genetic basis of adaptation.

Shifts in the intensity of purifying selection: an analysis of genome-wide polymorphism data from two closely related yeast species.

How much does the intensity of purifying selection vary among populations and species? How uniform are the shifts in selective pressures across the genome? To address these questions, we took advantage of a recent, whole-genome polymorphism data set from two closely related species of yeast, Saccharomyces cerevisiae and S. paradoxus, paying close attention to the population structure within these species. We found that the average intensity of purifying selection on amino acid sites varies markedly among populations and between species. As expected in the presence of extensive weakly deleterious mutations, the effect of purifying selection is substantially weaker on single nucleotide polymorphisms (SNPs) segregating within populations than on SNPs fixed between population samples. Also in accordance with a Nearly Neutral model, the variation in the intensity of purifying selection across populations corresponds almost perfectly to simple measures of their effective size. As a first step toward understanding the processes generating these patterns, we sought to tease apart the relative importance of systematic, genome-wide changes in the efficacy of selection, such as those expected from demographic processes and of gene-specific changes, which may be expected after a shift in selective pressures. For that purpose, we developed a new model for the evolution of purifying selection between populations and inferred its parameters from the genome-wide data using a likelihood approach. We found that most, but not all changes seem to be explained by systematic shifts in the efficacy of selection. One population, the sake-derived strains of S. cerevisiae, however, also shows extensive gene-specific changes, plausibly associated with domestication. These findings have important implications for our understanding of purifying selection as well as for estimates of the rate of molecular adaptation in yeast and in other species.

Broad-scale variation in human genetic diversity levels is predicted by purifying selection on coding and non-coding elements.

Analyses of genetic variation in many taxa have established that neutral genetic diversity is shaped by natural selection at linked sites. Whether the mode of selection is primarily the fixation of strongly beneficial alleles (selective sweeps) or purifying selection on deleterious mutations (background selection) remains unknown, however. We address this question in humans by fitting a model of the joint effects of selective sweeps and background selection to autosomal polymorphism data from the 1000 Genomes Project. After controlling for variation in mutation rates along the genome, a model of background selection alone explains ~60% of the variance in diversity levels at the megabase scale. Adding the effects of selective sweeps driven by adaptive substitutions to the model does not improve the fit, and when both modes of selection are considered jointly, selective sweeps are estimated to have had little or no effect on linked neutral diversity. The regions under purifying selection are best predicted by phylogenetic conservation, with ~80% of the deleterious mutations affecting neutral diversity occurring in non-exonic regions. Thus, background selection is the dominant mode of linked selection in humans, with marked effects on diversity levels throughout autosomes.

Clustering of 770,000 genomes reveals post-colonial population structure of North America.

Despite strides in characterizing human history from genetic polymorphism data, progress in identifying genetic signatures of recent demography has been limited. Here we identify very recent fine-scale population structure in North America from a network of over 500 million genetic (identity-by-descent, IBD) connections among 770,000 genotyped individuals of US origin. We detect densely connected clusters within the network and annotate these clusters using a database of over 20 million genealogical records. Recent population patterns captured by IBD clustering include immigrants such as Scandinavians and French Canadians; groups with continental admixture such as Puerto Ricans; settlers such as the Amish and Appalachians who experienced geographic or cultural isolation; and broad historical trends, including reduced north-south gene flow. Our results yield a detailed historical portrait of North America after European settlement and support substantial genetic heterogeneity in the United States beyond that uncovered by previous studies.

Classic selective sweeps were rare in recent human evolution.

Efforts to identify the genetic basis of human adaptations from polymorphism data have sought footprints of "classic selective sweeps" (in which a beneficial mutation arises and rapidly fixes in the population).Yet it remains unknown whether this form of natural selection was common in our evolution. We examined the evidence for classic sweeps in resequencing data from 179 human genomes. As expected under a recurrent-sweep model, we found that diversity levels decrease near exons and conserved noncoding regions. In contrast to expectation, however, the trough in diversity around human-specific amino acid substitutions is no more pronounced than around synonymous substitutions. Moreover, relative to the genome background, amino acid and putative regulatory sites are not significantly enriched in alleles that are highly differentiated between populations. These findings indicate that classic sweeps were not a dominant mode of human adaptation over the past ~250,000 years.