Meiotic DNA breaks drive multifaceted mutagenesis in the human germ line

• 成果类型: Article
• 署名作者: Hinch, Robert; Donnelly, Peter; Hinch, Anjali Gupta
• 署名单位: University of Oxford; University of Oxford; Wellcome Centre for Human Genetics
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8800
• DOI: 10.1126/science.adh2531
• 发表日期: 2023-12-01
• 页码: 1012-+
• 关键词: recombination hot-spots; double-strand breaks; gene conversion; mutational signatures; repair; prdm9; polymerase; rates; instability; crossover

摘要

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.