摘要
In renewing tissues,mutations conferring selective advantage may result in clonal expansions1-4.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 drivers5-8.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 conditions9-13,6,065 control trios12,14-19 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.
