Evidence for Hitchhiking of Deleterious Mutations within the Human Genome

Deleterious mutations present a significant obstacle to adaptive evolution. Deleterious mutations can inhibit the spread of linked adaptive mutations through a population; conversely, adaptive substitutions can increase the frequency of linked deleterious mutations and even result in their fixation. To assess the impact of adaptive mutations on linked deleterious mutations, we examined the distribution of deleterious and neutral amino acid polymorphism in the human genome. Within genomic regions that show evidence of recent hitchhiking, we find fewer neutral but a similar number of deleterious SNPs compared to other genomic regions. The higher ratio of deleterious to neutral SNPs is consistent with simulated hitchhiking events and implies that positive selection eliminates some deleterious alleles and increases the frequency of others. The distribution of disease-associated alleles is also altered in hitchhiking regions. Disease alleles within hitchhiking regions have been associated with auto-immune disorders, metabolic diseases, cancers, and mental disorders. Our results suggest that positive selection has had a significant impact on deleterious polymorphism and may be partly responsible for the high frequency of certain human disease alleles.有害突变（deleterious mutations）对适应性演化（adaptive evolution）构成显著阻碍。有害突变可抑制种群内连锁适应性突变（linked adaptive mutations）的扩散；反之，适应性替换（adaptive substitutions）则会提升连锁有害突变的频率，甚至使其达到固定状态。为评估适应性突变对连锁有害突变的影响，本研究分析了人类基因组中有害与中性氨基酸多态性的分布特征。在显示出近期遗传搭车（hitchhiking）信号的基因组区域中，相较于其他基因组区域，我们观察到中性多态性位点数量更少，但有害单核苷酸多态性位点（SNPs）的数量无显著差异。有害与中性SNPs的比值升高，这与模拟得到的遗传搭车事件结果相符，同时表明正选择（positive selection）会清除部分有害等位基因（deleterious alleles），并提升其余有害等位基因的频率。遗传搭车区域内疾病相关等位基因（disease-associated alleles）的分布同样发生改变。位于遗传搭车区域内的疾病等位基因与自身免疫性疾病（auto-immune disorders）、代谢性疾病、癌症及精神类疾病密切相关。本研究结果表明，正选择对有害多态性具有显著影响，且可能是部分人类疾病等位基因频率偏高的部分原因。