Negative linkage disequilibrium between amino acid changing variants reveals interference among deleterious mutations in the human genome.
Negative linkage disequilibrium between amino acid changing variants reveals interference among deleterious mutations in the human genome.
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DOI：
10.1371/journal.pgen.1009676
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发表时间：
2021-07
期刊：
影响因子：
4.5
通讯作者：
Lohmueller KE
中科院分区：
文献类型：
--
作者：
Garcia JA;Lohmueller KE
像Hill-Robertson干扰和负上位性这样的进化力量可以导致在不同的单倍型上发现有害的突变。然而，这些力量在多大程度上取决于选择和优势系数的有害突变和形状的全基因组连锁不平衡（LD）模式在自然人群中具有复杂的人口统计学历史尚未测试。在这项研究中，我们首先使用时间向前模拟来预测负面选择如何影响LD。在有害突变对适应性具有累加效应的模型下，相对于同义SNP对，相距小于10 kb的有害变体倾向于在不同的单倍型上携带。相反，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衰减没有一致的顺序。然后，我们检查了来自1000个基因组计划的现代人类的经验数据。与衍生的同义变体对相比，在非同义SNP处衍生的等位基因之间的LD较低，这表明非同义衍生的等位基因倾向于比同义变体更多地发生在不同的单倍型上。当通过匹配样本中的频率（等位基因计数）、物理距离、背景选择的幅度和变体对之间的遗传距离的SNP来控制潜在的混杂因素时，该结果成立。最后，我们引入了一个新的统计HR（j），它允许我们使用非定相基因型检测干扰。这种方法的高覆盖率的人类基因组序列的应用证实了我们的发现，即非同义衍生等位基因往往位于不同的单倍型更经常比同义衍生等位基因。我们的研究结果表明，干扰可能在人类基因组中有害变体之间形成LD模式中发挥普遍作用，从而影响LD的全基因组模式。基因组中的许多突变是有害的，降低了携带者的适应性。量化有害突变的流行方法独立地对突变进行建模，而忽略了附近变异之间的相关性。理论预测，有害的突变可以影响基因组沿着附近变异的频率变化。在这里，我们使用人口遗传模型与人类相关的参数下的模拟表明，对有害的突变位于彼此附近的基因组往往有不同的相关性，它们之间的中性进化的SNP对相比。具体而言，如果个体在一个变体处携带有害等位基因，则该个体在附近变体处携带有害等位基因的可能性较小。然后，我们在来自多个人群的低覆盖率和高覆盖率人类遗传变异数据集中搜索这些模式。我们发现，即使在控制了混杂因素之后，有害等位基因对在不同的个体中发现的频率也比相同频率的中性进化变体对更高。我们的研究结果表明，有害等位基因之间的干扰在整个人类基因组中很常见，这对推断人口统计学历史，自然选择以及将变异与复杂性状相关联具有重要意义。
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. Many mutations in genomes are deleterious, decreasing fitness in carriers. Popular methods to quantify deleterious mutations model mutations independently while ignoring the correlations between nearby variants. Theory predicts that a deleterious mutation can influence the frequency change of variants located nearby along the genome. Here we use simulations under population genetic models with parameters relevant to humans to show that pairs of deleterious mutations located near each other in the genome tend to have different correlations between them as compared to pairs of neutrally evolving SNPs. Specifically, if an individual carries the deleterious allele at one variant, that individual is less likely to carry the deleterious allele at a nearby variant. We then searched for these patterns in both low and high-coverage human genetic variation datasets from multiple populations. We found that pairs of deleterious alleles tend to be found in different individuals more frequently than are pairs of neutrally evolving variants at the same frequency, even after controlling for confounding factors. Our results suggest that the interference between deleterious alleles is common across the human genome, which has implications for inferring demographic history, natural selection, and associating variants with complex traits.
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DOI：
10.1073/pnas.0906182107
发表时间：
2010-01-26
影响因子：
11.1
作者：
Eyre-Walker, Adam
通讯作者：
Eyre-Walker, Adam
影响因子：
30.8
作者：
Bulik-Sullivan, Brendan K.;Loh, Po-Ru;Finucane, Hilary K.;Ripke, Stephan;Yang, Jian;Patterson, Nick;Daly, Mark J.;Price, Alkes L.;Neale, Benjamin M.
通讯作者：
Neale, Benjamin M.
影响因子：
30.8
作者：
Finucane HK;Bulik-Sullivan B;Gusev A;Trynka G;Reshef Y;Loh PR;Anttila V;Xu H;Zang C;Farh K;Ripke S;Day FR;ReproGen Consortium;Schizophrenia Working Group of the Psychiatric Genomics Consortium;RACI Consortium;Purcell S;Stahl E;Lindstrom S;Perry JR;Okada Y;Raychaudhuri S;Daly MJ;Patterson N;Neale BM;Price AL
通讯作者：
Price AL
影响因子：
7
作者：
Bullaughey, Kevin;Przeworski, Molly;Coop, Graham
通讯作者：
Coop, Graham
影响因子：
14.9
作者：
Deutsch, M;Long, M
通讯作者：
Long, M