Genome-wide sequencing of human populations has revealed substantial variation among genes in the intensity of purifying selection acting on damaging genetic variants¹. While genes under the strongest selective constraint are highly enriched for associations with Mendelian disorders, most of these genes are not associated with disease and therefore the nature of the selection acting on them is not known². Here we show that genetic variants that damage these genes are associated with markedly reduced reproductive success, primarily due to increased childlessness, with a stronger effect in males than in females. We present evidence that increased childlessness is likely mediated by genetically associated cognitive and behavioural traits, which may mean male carriers are less likely to find reproductive partners. This reduction in reproductive success may account for 20% of purifying selection against heterozygous variants that ablate protein-coding genes. While this genetic association could only account for a very minor fraction of the overall likelihood of being childless (less than 1%), especially when compared to more influential sociodemographic factors, it may influence how genes evolve over time.

中文翻译：

---

繁殖成功率降低与对人类基因的选择性限制有关

人类群体的全基因组测序揭示了基因之间在作用于破坏性遗传变异¹的纯化选择强度方面存在显着差异。虽然在最强选择性约束下的基因高度富集与孟德尔疾病的关联，但这些基因中的大多数与疾病无关，因此作用于它们的选择的性质尚不清楚². 在这里，我们表明破坏这些基因的遗传变异与生殖成功率显着降低有关，这主要是由于无子女的增加，对男性的影响比对女性的影响更大。我们提供的证据表明，增加的无子女可能是由遗传相关的认知和行为特征介导的，这可能意味着男性携带者不太可能找到生殖伴侣。这种繁殖成功率的降低可能占针对消除蛋白质编码基因的杂合变体的纯化选择的 20%。虽然这种遗传关联只占没有孩子的总体可能性的很小一部分（不到 1%），尤其是与更有影响力的社会人口因素相比时，它可能会影响基因如何随着时间的推移而进化。