稳定选择使复杂性状的尾部富含具有较大效应的稀有等位基因

Anil PS Ori, Carla Giner-Delgado, Clive Julian Hoggart, Paul F O'Reilly
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摘要

确定常见变异和罕见变异对复杂性状遗传性的相对贡献是生物医学研究的一个关键目标。最近的统计遗传学推断表明,常见变异解释了大多数复杂性状的遗传率,但人们对遗传结构在性状连续体中的变化知之甚少。如果罕见变异对遗传率的贡献很小,但其影响集中在复杂性状的尾部,而疾病通常就表现在尾部,那么它们对临床的影响可能比以前推断的更大。在这里,我们使用时间前向模拟器 SLiM 进行模拟,生成现实的群体遗传和复杂性状数据,其中性状在中性或稳定选择下进化。最近的研究表明,稳定选择是塑造复杂性状遗传结构的主导力量,这与我们的模拟结果一致,即在稳定选择下模拟的数据更接近真实数据。此外,我们观察到在稳定选择下,稀有的大效应等位基因会向复杂性状分布的尾部移动。在我们的模拟中,根据选择强度的不同,在稳定选择条件下,复杂性状尾部的个体携带单个或极其罕见的大效应等位基因的可能性是中性条件下的 10-20 倍。在实际复杂性状的尾部,稀有、大效应等位基因在稳定选择下的这种富集可能会对检测稀有变异的研究设计以及复杂疾病的预测和预防产生重要影响。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Stabilising selection enriches the tails of complex traits with rare alleles of large effect
Establishing the relative contribution of common and rare variants to complex trait heritability is a key goal of biomedical research. Recent statistical genetics inference suggests that common variants explain most complex trait heritability, but little is known about how genetic architecture varies across the trait continuum. If rare variants make a small contribution to heritability but have their effects concentrated in the tails of complex traits, where disease typically manifests, then they may have a greater clinical impact than previously inferred. Here, we perform simulations using the forward-in-time simulator SLiM to generate realistic population genetic and complex trait data, in which traits evolve under neutrality or stabilising selection. Recent studies suggest that stabilising selection is the dominant force shaping the genetic architecture of complex traits, consistent with our simulations in that data simulated under stabilising selection here more closely resembles real data. Moreover, we observe a shift of rare, large-effect alleles towards the tails of the complex trait distribution under stabilising selection. In our simulations, individuals in the tails of complex traits are, depending on the strength of selection, 10-20x more likely to harbour singleton or extremely rare alleles of large effect under stabilising selection than neutrality. Such an enrichment of rare, large-effect alleles in the tails of real complex traits subject to stabilising selection could have important implications for the design of studies to detect rare variants, as well as for the prediction and prevention of complex disease.
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