Interdepartmental Program in Bioinformatics, University of California, Los Angeles, California, United States of America.
Department of Ecology and Evolutionary Biology, University of California, Los Angeles, California, United States of America.
PLoS Genet. 2021 Jul 28;17(7):e1009676. doi: 10.1371/journal.pgen.1009676. eCollection 2021 Jul.
Evolutionary forces like Hill-Robertson interference and negative epistasis can lead to deleterious mutations being found on distinct haplotypes. However, the extent to which these forces depend on the selection and dominance coefficients of deleterious mutations and shape genome-wide patterns of linkage disequilibrium (LD) in natural populations with complex demographic histories has not been tested. In this study, we first used forward-in-time simulations to predict how negative selection impacts LD. Under models where deleterious mutations have additive effects on fitness, deleterious variants less than 10 kb apart tend to be carried on different haplotypes relative to pairs of synonymous SNPs. In contrast, for recessive mutations, there is no consistent ordering of how selection coefficients affect LD decay, due to the complex interplay of different evolutionary effects. We then examined empirical data of modern humans from the 1000 Genomes Project. LD between derived alleles at nonsynonymous SNPs is lower compared to pairs of derived synonymous variants, suggesting that nonsynonymous derived alleles tend to occur on different haplotypes more than synonymous variants. This result holds when controlling for potential confounding factors by matching SNPs for frequency in the sample (allele count), physical distance, magnitude of background selection, and genetic distance between pairs of variants. Lastly, we introduce a new statistic HR(j) which allows us to detect interference using unphased genotypes. Application of this approach to high-coverage human genome sequences confirms our finding that nonsynonymous derived alleles tend to be located on different haplotypes more often than are synonymous derived alleles. Our findings suggest that interference may play a pervasive role in shaping patterns of LD between deleterious variants in the human genome, and consequently influences genome-wide patterns of LD.
进化力量，如 Hill-Robertson 干扰和负遗传相互作用，可能导致有害突变出现在不同的单倍型上。然而，这些力量在多大程度上取决于有害突变的选择和显性系数，以及它们如何塑造具有复杂人口历史的自然种群中全基因组连锁不平衡（LD）的模式，尚未得到检验。在这项研究中，我们首先使用向前时间模拟来预测负选择对 LD 的影响。在有害突变对适合度具有加性效应的模型中，相距不到 10 kb 的有害变体相对于同义 SNP 对，往往携带在不同的单倍型上。相比之下，对于隐性突变，由于不同进化效应的复杂相互作用，选择系数如何影响 LD 衰减没有一致的排序。然后，我们检查了来自 1000 基因组计划的现代人类的实证数据。非同义 SNP 的衍生等位基因之间的 LD 低于同义 SNP 对之间的 LD，这表明非同义衍生等位基因比同义变体更倾向于出现在不同的单倍型上。当通过匹配样本中 SNP 的频率（等位基因计数）、物理距离、背景选择的幅度以及变体对之间的遗传距离来控制潜在混杂因素时，该结果仍然成立。最后，我们引入了一个新的统计量 HR(j)，它允许我们使用未相化基因型来检测干扰。该方法在高覆盖率人类基因组序列上的应用证实了我们的发现，即非同义衍生等位基因比同义衍生等位基因更倾向于位于不同的单倍型上。我们的研究结果表明，干扰可能在塑造人类基因组中有害变体之间 LD 的模式方面发挥普遍作用，进而影响全基因组 LD 的模式。
