St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065;
St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065.
Proc Natl Acad Sci U S A. 2021 Jan 19;118(3). doi: 10.1073/pnas.2001248118.
Genetic variants underlying life-threatening diseases, being unlikely to be transmitted to the next generation, are gradually and selectively eliminated from the population through negative selection. We study the determinants of this evolutionary process in human genes underlying monogenic diseases by comparing various negative selection scores and an integrative approach, CoNeS, at 366 loci underlying inborn errors of immunity (IEI). We find that genes underlying autosomal dominant (AD) or X-linked IEI have stronger negative selection scores than those underlying autosomal recessive (AR) IEI, whose scores are not different from those of genes not known to be disease causing. Nevertheless, genes underlying AR IEI that are lethal before reproductive maturity with complete penetrance have stronger negative selection scores than other genes underlying AR IEI. We also show that genes underlying AD IEI by loss of function have stronger negative selection scores than genes underlying AD IEI by gain of function, while genes underlying AD IEI by haploinsufficiency are under stronger negative selection than other genes underlying AD IEI. These results are replicated in 1,140 genes underlying inborn errors of neurodevelopment. Finally, we propose a supervised classifier, SCoNeS, which predicts better than state-of-the-art approaches whether a gene is more likely to underlie an AD or AR disease. The clinical outcomes of monogenic inborn errors, together with their mode and mechanisms of inheritance, determine the levels of negative selection at their corresponding loci. Integrating scores of negative selection may facilitate the prioritization of candidate genes and variants in patients suspected to carry an inborn error.
导致危及生命的疾病的遗传变异不太可能传递给下一代，而是通过负选择逐渐从人群中选择性地消除。我们通过比较各种负选择评分和综合方法 CoNeS，研究了导致单基因疾病的人类基因背后的这一进化过程的决定因素，该方法研究了 366 个导致先天性免疫缺陷（IEI）的基因。我们发现，与常染色体隐性（AR）IEI 相比，导致常染色体显性（AD）或 X 连锁 IEI 的基因具有更强的负选择评分，而 AR IEI 的评分与那些已知不会导致疾病的基因没有区别。然而，在生殖成熟前具有完全外显率且致死的 AR IEI 相关基因的负选择评分要强于其他 AR IEI 相关基因。我们还表明，AD IEI 相关基因因功能丧失而具有更强的负选择评分，而 AD IEI 相关基因因功能获得而具有更强的负选择评分，而 AD IEI 相关基因因杂合不足而具有更强的负选择评分，优于其他 AD IEI 相关基因。这些结果在 1140 个导致神经发育障碍的单基因疾病中得到了复制。最后，我们提出了一种监督分类器 SCoNeS，该分类器比最先进的方法更能预测一个基因是否更有可能导致 AD 或 AR 疾病。单基因先天性疾病的临床结局，以及它们的遗传方式和机制，决定了其相应基因座的负选择水平。整合负选择评分可能有助于优先考虑疑似携带先天性错误的患者的候选基因和变体。
