美国哈佛医学院Shamil Sunyaev研究小组提出了人类突变热点指向精原细胞的克隆扩增。相关论文于2025年10月8日发表在《自然》杂志上。

该课题组人员开发了一种系统的方法来发现作为人类新生突变热点的CES驱动因素。他们分析了54715个被确定为罕见疾病的三人组、6065个对照三人组，以及来自807162个大多数健康个体的群体变异，发现了与疾病确定的可接受模型不一致的新发突变率基因。课题组研究人员提出了23个在功能丧失（LoF）位点超可变的基因作为候选的CES驱动因素。

另外17个基因在个别位置具有超可变错义突变，表明CES通过功能获得起作用。在对照三人组和精子中，CES使LoF基因的平均突变率增加了大约17倍，在精子中，集合功能获得位点的平均突变率增加了大约500倍。男性生殖系的正向选择提高了遗传疾病的患病率，增加了多态性水平，掩盖了人类种群中负向选择的影响。尽管在19个LoF CES驱动候选者的疾病队列中存在过多的突变，但只有9个显示出疾病遗传性的明确证据，这表明CES可能导致假阳性的疾病关联。

研究人员表示，在组织更新中，具有选择优势的突变可能导致克隆扩张。与体细胞组织不同，驱动精原细胞（CES）克隆扩增的突变也会遗传给下一代。这导致CES驱动器的从头突变率有效增加。CES最初是通过Apert综合征中新生突变的极端复发发现的。

附：英文原文

Title: Hotspots of human mutation point to clonal expansions in spermatogonia

Author: Seplyarskiy, Vladimir, Moldovan, Mikhail A., Koch, Evan, Kar, Prathitha, Neville, Matthew D. C., Rahbari, Raheleh, Sunyaev, Shamil

Issue&Volume: 2025-10-08

Abstract: In renewing tissues, mutations conferring selective advantage may result in clonal expansions1,2,3,4. In contrast to somatic tissues, mutations driving clonal expansions in spermatogonia (CES) are also transmitted to the next generation. This results in an effective increase of de novo mutation rate for CES drivers5,6,7,8. CES was originally discovered through extreme recurrence of de novo mutations causing Apert syndrome5. Here, we develop a systematic approach to discover CES drivers as hotspots of human de novo mutation. Our analysis of 54,715 trios ascertained for rare conditions9,10,11,12,13, 6,065 control trios12,14,15,16,17,18,19 and population variation from 807,162 mostly healthy individuals20 identifies genes manifesting rates of de novo mutations inconsistent with plausible models of disease ascertainment. We propose 23 genes hypermutable at loss-of-function (LoF) sites as candidate CES drivers. An extra 17 genes feature hypermutable missense mutations at individual positions, suggesting CES acting through gain of function. CES increases the average mutation rate roughly 17-fold for LoF genes in both control trios and sperm and roughly 500-fold for pooled gain-of-function sites in sperm21. Positive selection in the male germline elevates the prevalence of genetic disorders and increases polymorphism levels, masking the effect of negative selection in human populations. Despite the excess of mutations in disease cohorts for 19 LoF CES driver candidates, only 9 show clear evidence of disease causality22, suggesting that CES may lead to false-positive disease associations.

DOI: 10.1038/s41586-025-09579-7

Source: https://www.nature.com/articles/s41586-025-09579-7