RT Journal Article SR Electronic T1 Germline de novo mutation clusters arise during oocyte aging in genomic regions with increased double-strand break incidence JF bioRxiv FD Cold Spring Harbor Laboratory SP 140111 DO 10.1101/140111 A1 Jakob M. Goldmann A1 Vladimir B. Seplyarskiy A1 Wendy S.W. Wong A1 Thierry Vilboux A1 Dale L. Bodian A1 Benjamin D. Solomon A1 Joris A. Veltman A1 John F. Deeken A1 Christian Gilissen A1 John E. Niederhuber YR 2017 UL http://biorxiv.org/content/early/2017/06/30/140111.abstract AB Clustering of mutations has been found both in somatic mutations from cancer genomes and in germline de novo mutations (DNMs). We identified 1,755 clustered DNMs (cDNMs) within whole-genome sequencing data from 1,291 parent-offspring trios and investigated the underlying mutational mechanisms. We found that the number of clusters on the maternalallele was positively correlated with maternal age and that these consist of more individual mutations with larger intra-mutational distances compared to paternal clusters. More than 50% of maternal clusters were located on chromosomes 8, 9 and 16, in regions with an overall increased maternal mutation rate. Maternal clusters in these regions showed a distinct mutation signature characterized by C>G mutations. Finally, we found that maternal clusters associate with processes involving double-stranded-breaks (DSBs) such as meiotic gene conversions and de novo deletions events. These findings suggest accumulation of DSB-induced mutations throughout oocyte aging as an underlying mechanism leading to maternal mutation clusters.