Institute of Ecology and Evolution, University of Oregon, Eugene, OR 97403, USA.
Department of Ecology and Evolutionary Biology, University of Toronto, Toronto, ON M5S 3B2, Canada.
Genetics. 2021 Mar 3;217(1):1-10. doi: 10.1093/genetics/iyaa015.
Sex and sexual differentiation are pervasive across the tree of life. Because females and males often have substantially different functional requirements, we expect selection to differ between the sexes. Recent studies in diverse species, including humans, suggest that sexually antagonistic viability selection creates allele frequency differences between the sexes at many different loci. However, theory and population-level simulations indicate that sex-specific differences in viability would need to be very large to produce and maintain reported levels of between-sex allelic differentiation. We address this contradiction between theoretical predictions and empirical observations by evaluating evidence for sexually antagonistic viability selection on autosomal loci in humans using the largest cohort to date (UK Biobank, n = 487,999) along with a second large, independent cohort (BioVU, n = 93,864). We performed association tests between genetically ascertained sex and autosomal loci. Although we found dozens of genome-wide significant associations, none replicated across cohorts. Moreover, closer inspection revealed that all associations are likely due to cross-hybridization with sex chromosome regions during genotyping. We report loci with potential for mis-hybridization found on commonly used genotyping platforms that should be carefully considered in future genetic studies of sex-specific differences. Despite being well powered to detect allele frequency differences of up to 0.8% between the sexes, we do not detect clear evidence for this signature of sexually antagonistic viability selection on autosomal variation. These findings suggest a lack of strong ongoing sexually antagonistic viability selection acting on single locus autosomal variation in humans.
性和性分化在生命之树上无处不在。由于女性和男性通常具有明显不同的功能需求，我们期望选择会在两性之间有所不同。最近在包括人类在内的多种物种中的研究表明，性拮抗生存选择会在许多不同的基因座上造成两性之间等位基因频率的差异。然而，理论和群体水平的模拟表明，生存能力的性别特异性差异需要非常大，才能产生并维持报告的性别间等位基因分化水平。我们通过使用迄今为止最大的队列（英国生物银行，n=487999）以及第二个大型独立队列（BioVU，n=93864）来评估人类常染色体基因座上的性拮抗生存选择的证据，从而解决了理论预测与经验观察之间的这种矛盾。我们对通过遗传确定的性别与常染色体基因座之间进行了关联测试。尽管我们发现了几十个全基因组显著关联，但没有一个在两个队列中都能重复。此外，更仔细的检查表明，所有的关联都可能是由于在基因分型过程中与性染色体区域的交叉杂交所致。我们报告了在常用基因分型平台上发现的可能发生杂交错误的基因座，在未来的性别差异遗传研究中应谨慎考虑。尽管我们有足够的能力检测两性之间等位基因频率差异高达 0.8%的差异，但我们没有发现明显的证据表明这种性拮抗生存选择的特征存在于常染色体变异上。这些发现表明，在人类中，没有强烈的持续的性拮抗生存选择作用于单个常染色体基因座的变异。
