Genetic and chemotherapeutic causes of germline hypermutation
Genetic and chemotherapeutic causes of germline hypermutation
Summary Mutation in the germline is the source of all evolutionary genetic variation and a cause of genetic disease. Previous studies have shown parental age to be the primary determinant of the number of new germline mutations seen in an individual’s genome. Here we analysed the genome-wide sequences of 21,879 families with rare genetic diseases and identified 12 hypermutated individuals with between two and seven times more de novo single nucleotide variants (dnSNVs) than expected. In most of these families (8/12) the excess mutations could be attributed to the father. We determined that two of these families had genetic drivers of germline hypermutation, with the fathers carrying damaging genetic variation in known DNA repair genes, causing distinctive mutational signatures. For five families, by analysing clinical records and mutational signatures, we determined that paternal exposure to chemotherapeutic agents prior to conception was a key driver of hypermutation. Our results suggest that the germline is well protected from mutagenic effects, hypermutation is rare and relatively modest in degree and that most hypermutated individuals will not have a genetic disease.
Barnicoat Angela、O?ˉBrien Patrick、Carmichael Jenny、Ide Benjamin、Sanghvi Rashesh、Danecek Petr、Moutsianas Loukas、Prigmore Elena、Short Patrick、McRae Jeremy、Firth Helen、Kaplanis Joanna、Hurles Matthew、Genomics England Research Consortium、Coorens Tim、Gallone Giuseppe、Rahbari Raheleh、Odhams Chris、Neville Matthew
North East Thames Regional Genetics Service, Great Ormond Street HospitalDepartment of Biological Chemistry, University of MichiganEast Anglian Medical Genetics Service, Cambridge University HospitalsDepartment of Biological Chemistry, University of MichiganWellcome Sanger Institute, Wellcome Genome CampusWellcome Sanger Institute, Wellcome Genome CampusGenomics EnglandWellcome Sanger Institute, Wellcome Genome CampusWellcome Sanger Institute, Wellcome Genome CampusWellcome Sanger Institute, Wellcome Genome CampusWellcome Sanger Institute, Wellcome Genome Campus||East Anglian Medical Genetics Service, Cambridge University HospitalsWellcome Sanger Institute, Wellcome Genome CampusWellcome Sanger Institute, Wellcome Genome CampusWellcome Sanger Institute, Wellcome Genome CampusWellcome Sanger Institute, Wellcome Genome CampusWellcome Sanger Institute, Wellcome Genome CampusGenomics EnglandWellcome Sanger Institute, Wellcome Genome Campus
遗传学基础医学医学研究方法
Barnicoat Angela,O?ˉBrien Patrick,Carmichael Jenny,Ide Benjamin,Sanghvi Rashesh,Danecek Petr,Moutsianas Loukas,Prigmore Elena,Short Patrick,McRae Jeremy,Firth Helen,Kaplanis Joanna,Hurles Matthew,Genomics England Research Consortium,Coorens Tim,Gallone Giuseppe,Rahbari Raheleh,Odhams Chris,Neville Matthew.Genetic and chemotherapeutic causes of germline hypermutation[EB/OL].(2025-03-28)[2025-05-04].https://www.biorxiv.org/content/10.1101/2021.06.01.446180.点此复制
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