Determining the Effect of Natural Selection on Linked Neutral Divergence across Species

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.

进化生物学的一项核心目标，在于阐明自然选择如何塑造全基因组的遗传变异格局。针对多个物种的研究表明，与直接受选择位点连锁的区域内，中性遗传多样性（neutral genetic diversity，即种内差异）水平会出现降低。不过，连锁选择对中性序列分化（neutral sequence divergence，即种间差异）的影响仍不明确。尽管实证研究报道了分化与重组之间存在相关性，并将其解读为自然选择降低连锁中性分化的证据，但理论研究却得出了相反的结论，尤其是对于分化时间久远的物种而言。本研究通过检验自然选择能否影响近缘及远缘物种间的序列分化，来解决这些悬而未决的问题。我们发现，近缘物种（例如人与灵长类）间的中性序列分化与功能区域含量呈负相关，与人类基因组的重组率呈正相关。我们还发现，远缘物种（例如人与啮齿类）间的中性序列分化与功能区域含量呈负相关，与灵长类的背景选择（background selection）估计值呈正相关。在控制了高突变CpG位点、GC含量以及偏倚基因转换等混杂因素后，上述模式依然成立。溯祖模型（coalescent models）显示，即便祖先多态性对序列分化的贡献较小，祖先种群中的背景选择仍可解释全基因组序列分化方差的大部分，从而产生观测到的相关性。我们的研究结果表明，与以往的认知相反，自然选择可间接影响近缘与远缘物种间的连锁中性序列分化。尽管我们无法从形式上排除净化选择（purifying selection）的直接效应促成部分观测模式的可能性，但该情景仅在基因组中受净化选择的区域多于当前认知的前提下才有可能成立。本研究对于理解基因组进化及解读遗传变异格局具有重要意义。