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

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.

Overlooked roles of DNA damage and maternal age in generating human germline mutations

“…The same association is not seen for short deletions or insertions (<5bp), however (Table S4), which are more likely to arise from replication slippage (Montgomery et al, 2013;Kloosterman et al, 2015). Together, these observations support imperfect repair of double-strand breaks as an important source of C>G transversions in both sexes (Jónsson, Sulem, Kehr, et al, 2017;Goldmann et al, 2018;I. Agarwal and M. Przeworski, unpublished results).…”

“…Based on their spatial distribution in the genome and their increase with maternal age, maternal C>G mutations were hypothesized to be associated with double-strand breaks (DSB) in aging oocytes: this mutation type often appears in clusters with strong strand-concordance and near de novo copy number variant breakpoints and is enriched in genomic regions with elevated rates of non-crossover gene conversion-an enrichment that increases rapidly with maternal age (Jónsson, Sulem, Kehr, et al, 2017;Goldmann et al, 2018). C>G mutations are also more frequent in the human pseudo-autosomal 1 region, which experiences an obligate crossover in males, than on autosomes and the rest of the X chromosome (I. Agarwal and M. Przeworski, unpublished results).…”

Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program

“…Some of these variants likely result from hypermutability of single-stranded DNA intermediates during repair of double-strand breaks 43,44 and are enriched for C>G transversions. They show prominent subtelomeric concentrations on chromosomes 8p, 9p, 16p, and 16q 43,44 ( Figures 2B and 2C, Supplementary Figure 9), consistent with evidence that subtelomeric regions are enriched for double-strand breaks in eukaryotic genomes 45 . Class 3 singletons occurring~30,000 -50,000 bp apart accounted for ~43-49% of all singletons.…”

Human Amniotic Fluid Mesenchymal Stem Cells Improve Ovarian Function During Physiological Aging by Resisting DNA Damage

“…Persistent senescent cells are generated by different situations related to human health throughout organismal life: age-related disease, natural aging, and therapeutic intervention-induced aging (Childs et al, 2015). DNA damage is a particularly problematic issue for nondividing or slow cell cleavage, where unrepaired damage can cumulate over time (Goldmann et al, 2018). In proliferating hGCs, an uncapped free double-stranded chromosome end is ultimately exposed by progressive telomere erosion and triggers a permanent DNA damage response (DDR) (Marangos et al, 2015).…”