Show simple item record

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.accessioned2022-05-18T15:00:52Z
dc.date.available2022-05-18T15:00:52Z
dc.date.issued2022-05
dc.date.submitted2021-06-01
dc.identifier.issn0028-0836
dc.identifier.others41586-022-04712-2
dc.identifier.other4712
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/337273
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.languageen
dc.publisherNature Publishing Group UK
dc.subjectArticle
dc.subject/631/208/212
dc.subject/631/208/737
dc.subject/631/208/366
dc.subject/631/208/1516
dc.subject/45
dc.subject/45/23
dc.subject/82
dc.subjectarticle
dc.titleGenetic and chemotherapeutic influences on germline hypermutation.
dc.typeArticle
dc.date.updated2022-05-18T15:00:52Z
prism.endingPage508
prism.issueIdentifier7910
prism.publicationNameNature
prism.startingPage503
prism.volume605
dc.identifier.doi10.17863/CAM.84688
dcterms.dateAccepted2022-03-31
rioxxterms.versionofrecord10.1038/s41586-022-04712-2
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://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


Files in this item

Thumbnail
Thumbnail
Thumbnail
Thumbnail
Thumbnail
Thumbnail

This item appears in the following Collection(s)

Show simple item record