title: Determining the Effect of Natural Selection on Linked Neutral Divergence across Species.
abstract: 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.
authors: Interdepartmental Program in Bioinformatics, University of California, Los Angeles, Los Angeles, California, United States of America.
authors: Tanya N
authors: TN
authors: Phung
authors: Department of Ecology and Evolutionary Biology, University of California, Los Angeles, Los Angeles, California, United States of America.
authors: Christian D
authors: 0000-0002-2267-2604
authors: CD
authors: Huber
authors: Interdepartmental Program in Bioinformatics, University of California, Los Angeles, Los Angeles, California, United States of America.|Department of Ecology and Evolutionary Biology, University of California, Los Angeles, Los Angeles, California, United States of America.|Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, United States of America.
authors: Kirk E
authors: KE
authors: Lohmueller
mesh_terms: D000818:Animals; D018899:CpG Islands / Q000235:genetics; D019143:Evolution, Molecular; D005785:Gene Conversion / Q000235:genetics; D040961:Genetic Drift; D014644:Genetic Variation; D016678:Genome; D006801:Humans; D009154:Mutation / Q000235:genetics; D011110:Polymorphism, Genetic; D011323:Primates / Q000235:genetics; D011995:Recombination, Genetic; D012377:Rodentia / Q000235:genetics; D012641:Selection, Genetic / Q000235:genetics*; D013045:Species Specificity