Meiotic DNA breaks drive multifaceted mutagenesis in the human germ line.
Journal
Science (New York, N.Y.)
ISSN: 1095-9203
Titre abrégé: Science
Pays: United States
ID NLM: 0404511
Informations de publication
Date de publication:
12 2023
12 2023
Historique:
medline:
4
12
2023
pubmed:
30
11
2023
entrez:
30
11
2023
Statut:
ppublish
Résumé
Meiotic recombination commences with hundreds of programmed DNA breaks; however, the degree to which they are accurately repaired remains poorly understood. We report that meiotic break repair is eightfold more mutagenic for single-base substitutions than was previously understood, leading to de novo mutation in one in four sperm and one in 12 eggs. Its impact on indels and structural variants is even higher, with 100- to 1300-fold increases in rates per break. We uncovered new mutational signatures and footprints relative to break sites, which implicate unexpected biochemical processes and error-prone DNA repair mechanisms, including translesion synthesis and end joining in meiotic break repair. We provide evidence that these mechanisms drive mutagenesis in human germ lines and lead to disruption of hundreds of genes genome wide.
Identifiants
pubmed: 38033082
doi: 10.1126/science.adh2531
pmc: PMC7615360
mid: EMS191910
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
eadh2531Subventions
Organisme : Wellcome Trust
ID : 203141
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 095552
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 221761
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 090532
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
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