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Genetic and chemotherapeutic influences on germline hypermutation

Mutations 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 genome(1,2). Here we analysed the genome-wide sequences of 21,879 families with rare genetic di...

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Autores principales: Kaplanis, Joanna, Ide, Benjamin, Sanghvi, Rashesh, Neville, Matthew, Danecek, Petr, Coorens, Tim, Prigmore, Elena, Short, Patrick, Gallone, Giuseppe, McRae, Jeremy, Carmichael, Jenny, Barnicoat, Angela, Firth, Helen, O’Brien, Patrick, Rahbari, Raheleh, Hurles, Matthew
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9117138/
https://www.ncbi.nlm.nih.gov/pubmed/35545669
http://dx.doi.org/10.1038/s41586-022-04712-2
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author Kaplanis, Joanna
Ide, Benjamin
Sanghvi, Rashesh
Neville, Matthew
Danecek, Petr
Coorens, Tim
Prigmore, Elena
Short, Patrick
Gallone, Giuseppe
McRae, Jeremy
Carmichael, Jenny
Barnicoat, Angela
Firth, Helen
O’Brien, Patrick
Rahbari, Raheleh
Hurles, Matthew
author_facet Kaplanis, Joanna
Ide, Benjamin
Sanghvi, Rashesh
Neville, Matthew
Danecek, Petr
Coorens, Tim
Prigmore, Elena
Short, Patrick
Gallone, Giuseppe
McRae, Jeremy
Carmichael, Jenny
Barnicoat, Angela
Firth, Helen
O’Brien, Patrick
Rahbari, Raheleh
Hurles, Matthew
author_sort Kaplanis, Joanna
collection PubMed
description Mutations 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 genome(1,2). 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.
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spelling pubmed-91171382022-05-20 Genetic and chemotherapeutic influences on germline hypermutation Kaplanis, Joanna Ide, Benjamin Sanghvi, Rashesh Neville, Matthew Danecek, Petr Coorens, Tim Prigmore, Elena Short, Patrick Gallone, Giuseppe McRae, Jeremy Carmichael, Jenny Barnicoat, Angela Firth, Helen O’Brien, Patrick Rahbari, Raheleh Hurles, Matthew Nature Article Mutations 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 genome(1,2). 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. Nature Publishing Group UK 2022-05-11 2022 /pmc/articles/PMC9117138/ /pubmed/35545669 http://dx.doi.org/10.1038/s41586-022-04712-2 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Kaplanis, Joanna
Ide, Benjamin
Sanghvi, Rashesh
Neville, Matthew
Danecek, Petr
Coorens, Tim
Prigmore, Elena
Short, Patrick
Gallone, Giuseppe
McRae, Jeremy
Carmichael, Jenny
Barnicoat, Angela
Firth, Helen
O’Brien, Patrick
Rahbari, Raheleh
Hurles, Matthew
Genetic and chemotherapeutic influences on germline hypermutation
title Genetic and chemotherapeutic influences on germline hypermutation
title_full Genetic and chemotherapeutic influences on germline hypermutation
title_fullStr Genetic and chemotherapeutic influences on germline hypermutation
title_full_unstemmed Genetic and chemotherapeutic influences on germline hypermutation
title_short Genetic and chemotherapeutic influences on germline hypermutation
title_sort genetic and chemotherapeutic influences on germline hypermutation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9117138/
https://www.ncbi.nlm.nih.gov/pubmed/35545669
http://dx.doi.org/10.1038/s41586-022-04712-2
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