Germline de novo mutation clusters arise during oocyte aging in genomic regions with high double-strand-break incidence

Nat Genet. 2018 Apr;50(4):487-492. doi: 10.1038/s41588-018-0071-6. Epub 2018 Mar 5.

Abstract

Clustering of mutations has been observed in cancer genomes as well as for germline de novo mutations (DNMs). We identified 1,796 clustered DNMs (cDNMs) within whole-genome-sequencing data from 1,291 parent-offspring trios to investigate their patterns and infer a mutational mechanism. We found that the number of clusters on the maternal allele was positively correlated with maternal age and that these clusters consisted of more individual mutations with larger intermutational distances than those of paternal clusters. More than 50% of maternal clusters were located on chromosomes 8, 9 and 16, in previously identified regions with accelerated maternal mutation rates. Maternal clusters in these regions showed a distinct mutation signature characterized by C>G transversions. Finally, we found that maternal clusters were associated with processes involving double-strand-breaks (DSBs), such as meiotic gene conversions and de novo deletion events. This result suggested accumulation of DSB-induced mutations throughout oocyte aging as the mechanism underlying the formation of maternal mutation clusters.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Cellular Senescence / genetics*
  • Cohort Studies
  • DNA Breaks, Double-Stranded*
  • DNA Copy Number Variations
  • Databases, Genetic
  • Female
  • Germ-Line Mutation*
  • Humans
  • Infant, Newborn
  • Male
  • Maternal Age
  • Middle Aged
  • Multigene Family
  • Oocytes / cytology*
  • Oocytes / metabolism*
  • Paternal Age
  • Polymorphism, Single Nucleotide
  • Young Adult