The lingering effects of Neanderthal introgression on human complex traits.
The lingering effects of Neanderthal introgression on human complex traits.
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DOI：
10.7554/elife.80757
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发表时间：
2023-03-20
期刊：
影响因子：
7.7
通讯作者：
Sankararaman S
中科院分区：
文献类型：
--
作者：
Wei X;Robles CR;Pazokitoroudi A;Ganna A;Gusev A;Durvasula A;Gazal S;Loh PR;Reich D;Sankararaman S
通过与尼安德特人杂交而引入现代人祖先的遗传变异被认为对复杂的人类特征做出了意想不到的贡献。然而，由于渗入变体的特异性群体遗传特性，测试该假设具有挑战性。我们开发了严格的方法来评估渗入的尼安德特人变体对遗传性状变异的贡献，并应用这些方法分析了英国生物库中约30万名无关的白色英国人中测量的235，592种渗入的尼安德特人变体和96种不同的表型。渗入的尼安德特人变体对性状变异做出了重大贡献（平均解释0.12%的性状变异）。然而，相对于与等位基因频率和连锁不平衡相匹配的现代人类变体，渗入变体的贡献倾向于显著耗尽（平均约59%耗尽），这与对渗入变体的纯化选择一致。与以前的研究不同（麦克阿瑟等人，2021），我们没有发现在检查的表型中遗传力升高的证据。我们确定了348个独立的显着协会渗入尼安德特人变异与64表型。先前的工作（Skov等人，2020）表明，大多数这种关联可能是由与附近的现代人类变异的统计关联驱动的，这些变异是真正的因果变异。应用定制的精细图谱，我们识别了47种表型的112个区域，其中包含4303个独特的遗传变异，其中基因渗入的变异极有可能产生表型效应。对这些变异的研究揭示了它们对免疫系统、发育和代谢重要基因的实质性影响。
The genetic variants introduced into the ancestors of modern humans from interbreeding with Neanderthals have been suggested to contribute an unexpected extent to complex human traits. However, testing this hypothesis has been challenging due to the idiosyncratic population genetic properties of introgressed variants. We developed rigorous methods to assess the contribution of introgressed Neanderthal variants to heritable trait variation and applied these methods to analyze 235,592 introgressed Neanderthal variants and 96 distinct phenotypes measured in about 300,000 unrelated white British individuals in the UK Biobank. Introgressed Neanderthal variants make a significant contribution to trait variation (explaining 0.12% of trait variation on average). However, the contribution of introgressed variants tends to be significantly depleted relative to modern human variants matched for allele frequency and linkage disequilibrium (about 59% depletion on average), consistent with purifying selection on introgressed variants. Different from previous studies (McArthur et al., 2021), we find no evidence for elevated heritability across the phenotypes examined. We identified 348 independent significant associations of introgressed Neanderthal variants with 64 phenotypes. Previous work (Skov et al., 2020) has suggested that a majority of such associations are likely driven by statistical association with nearby modern human variants that are the true causal variants. Applying a customized fine-mapping led us to identify 112 regions across 47 phenotypes containing 4303 unique genetic variants where introgressed variants are highly likely to have a phenotypic effect. Examination of these variants reveals their substantial impact on genes that are important for the immune system, development, and metabolism.