Contributions of Protein-Coding and Regulatory Change to Adaptive Molecular Evolution in Murid Rodents

摘要

The contribution of regulatory versus protein change to adaptive evolution has long been controversial. In principle, the rate and strength of adaptation within functional genetic elements can be quantified on the basis of an excess of nucleotide substitutions between species compared to the neutral expectation or from effects of recent substitutions on nucleotide diversity at linked sites. Here, we infer the nature of selective forces acting in proteins, their UTRs and conserved noncoding elements (CNEs) using genome-wide patterns of diversity in wild house mice and divergence to related species. By applying an extension of the McDonald-Kreitman test, we infer that adaptive substitutions are widespread in protein-coding genes, UTRs and CNEs, and we estimate that there are at least four times as many adaptive substitutions in CNEs and UTRs as in proteins. We observe pronounced reductions in mean diversity around nonsynonymous sites (whether or not they have experienced a recent substitution). This can be explained by selection on multiple, linked CNEs and exons. We also observe substantial dips in mean diversity (after controlling for divergence) around protein-coding exons and CNEs, which can also be explained by the combined effects of many linked exons and CNEs. A model of background selection (BGS) can adequately explain the reduction in mean diversity observed around CNEs. However, BGS fails to explain the wide reductions in mean diversity surrounding exons (encompassing ～100 Kb, on average), implying that there is a substantial role for adaptation within exons or closely linked sites. The wide dips in diversity around exons, which are hard to explain by BGS, suggest that the fitness effects of adaptive amino acid substitutions could be substantially larger than substitutions in CNEs. We conclude that although there appear to be many more adaptive noncoding changes, substitutions in proteins may dominate phenotypic evolution. Author Summary We present an analysis of the genome sequences of multiple wild house mice. Wild house mice are about ten times more genetically diverse than humans, reflecting the large effective population size of the species. This manifests itself as more effective natural selection acting against deleterious mutations and favouring advantageous mutations in mice than in humans. We show that there are strong signals of adaptive evolution at many sites in the genome. We estimate that 80% of adaptive changes in the genome are in gene regulatory elements and only 20% are in protein-coding genes. We find that nucleotide diversity is markedly reduced close to gene regulatory elements and protein-coding gene sequences. The reductions around regulatory elements can be explained by selection purging deleterious mutations that occur in the elements themselves, but this process only partially explains the diversity reductions around protein-coding genes. Recurrent adaptive evolution, which can also cause local reductions in diversity via selective sweeps, may be necessary to fully explain the patterns in diversity that we observe surrounding genes. Although most adaptive molecular evolution appears to be regulatory, adaptive phenotypic change may principally be driven by structural change in proteins.