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dc.contributor.authorKaplanis, Joanna
dc.contributor.authorIde, Benjamin
dc.contributor.authorSanghvi, Rashesh
dc.contributor.authorNeville, Matthew
dc.contributor.authorDanecek, Petr
dc.contributor.authorCoorens, Tim
dc.contributor.authorPrigmore, Elena
dc.contributor.authorShort, Patrick
dc.contributor.authorGallone, Giuseppe
dc.contributor.authorMcRae, Jeremy
dc.contributor.authorGenomics England Research Consortium
dc.contributor.authorCarmichael, Jenny
dc.contributor.authorBarnicoat, Angela
dc.contributor.authorFirth, Helen
dc.contributor.authorO'Brien, Patrick
dc.contributor.authorRahbari, Raheleh
dc.contributor.authorHurles, Matthew
dc.date.accessioned2022-06-12T01:06:28Z
dc.date.available2022-06-12T01:06:28Z
dc.date.issued2022-05
dc.identifier.issn0028-0836
dc.identifier.other35545669
dc.identifier.otherPMC9117138
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/338023
dc.descriptionFunder: British Heart Foundation
dc.description.abstractMutations in the germline generates all evolutionary genetic variation and is a cause of genetic disease. Parental age is the primary determinant of the number of new germline mutations in an individual's genome1,2. Here we analysed the genome-wide sequences of 21,879 families with rare genetic diseases and identified 12 individuals with a hypermutated genome with between two and seven times more de novo single-nucleotide variants than expected. In most families (9 out of 12), the excess mutations came from the father. Two families had genetic drivers of germline hypermutation, with fathers carrying damaging genetic variation in DNA-repair genes. For five of the families, paternal exposure to chemotherapeutic agents before conception was probably a key driver of hypermutation. Our results suggest that the germline is well protected from mutagenic effects, hypermutation is rare, the number of excess mutations is relatively modest and most individuals with a hypermutated genome will not have a genetic disease.
dc.languageeng
dc.publisherSpringer Science and Business Media LLC
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.sourcenlmid: 0410462
dc.sourceessn: 1476-4687
dc.subjectGerm Cells
dc.subjectHumans
dc.subjectGenetic Diseases, Inborn
dc.subjectParents
dc.subjectAge Factors
dc.subjectMutagenesis
dc.subjectMutation
dc.subjectGerm-Line Mutation
dc.subjectPolymorphism, Single Nucleotide
dc.subjectMale
dc.titleGenetic and chemotherapeutic influences on germline hypermutation.
dc.typeArticle
dc.date.updated2022-06-12T01:06:28Z
prism.endingPage508
prism.issueIdentifier7910
prism.publicationNameNature
prism.startingPage503
prism.volume605
dc.identifier.doi10.17863/CAM.85428
dcterms.dateAccepted2022-03-31
rioxxterms.versionofrecord10.1038/s41586-022-04712-2
rioxxterms.versionVoR
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0/
dc.contributor.orcidSanghvi, Rashesh [0000-0002-7703-9216]
dc.contributor.orcidNeville, Matthew [0000-0001-5816-7936]
dc.contributor.orcidCoorens, Tim [0000-0002-5826-3554]
dc.contributor.orcidPrigmore, Elena [0000-0001-8870-0316]
dc.contributor.orcidMcRae, Jeremy [0000-0003-3411-9248]
dc.contributor.orcidO'Brien, Patrick [0000-0001-7853-8626]
dc.contributor.orcidRahbari, Raheleh [0000-0002-1839-7785]
dc.contributor.orcidHurles, Matthew [0000-0002-2333-7015]
dc.identifier.eissn1476-4687
pubs.funder-project-idWellcome Trust (206194)
cam.issuedOnline2022-05-11


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International