Genetic and chemotherapeutic influences on germline hypermutation

Joanna Kaplanis, Benjamin Ide, Rashesh Sanghvi, Matthew Neville, Petr Danecek, Tim Coorens, Elena Prigmore, Patrick Short, Giuseppe Gallone, Jeremy McRae, Jenny Carmichael, Angela Barnicoat, Helen Firth, Patrick O’Brien, Raheleh Rahbari and Matthew Hurles ()
Additional contact information
Joanna Kaplanis: Wellcome Sanger Institute, Wellcome Genome Campus
Benjamin Ide: University of Michigan
Rashesh Sanghvi: Wellcome Sanger Institute, Wellcome Genome Campus
Matthew Neville: Wellcome Sanger Institute, Wellcome Genome Campus
Petr Danecek: Wellcome Sanger Institute, Wellcome Genome Campus
Tim Coorens: Wellcome Sanger Institute, Wellcome Genome Campus
Elena Prigmore: Wellcome Sanger Institute, Wellcome Genome Campus
Patrick Short: Wellcome Sanger Institute, Wellcome Genome Campus
Giuseppe Gallone: Wellcome Sanger Institute, Wellcome Genome Campus
Jeremy McRae: Wellcome Sanger Institute, Wellcome Genome Campus
Jenny Carmichael: Cambridge University Hospitals
Angela Barnicoat: Great Ormond Street Hospital
Helen Firth: Wellcome Sanger Institute, Wellcome Genome Campus
Patrick O’Brien: University of Michigan
Raheleh Rahbari: Wellcome Sanger Institute, Wellcome Genome Campus
Matthew Hurles: Wellcome Sanger Institute, Wellcome Genome Campus

Nature, 2022, vol. 605, issue 7910, 503-508

Abstract: Abstract 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 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.

Date: 2022
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41586-022-04712-2 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:605:y:2022:i:7910:d:10.1038_s41586-022-04712-2

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-022-04712-2

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().