PT - JOURNAL ARTICLE AU - Jakob M. Goldmann AU - Vladimir B. Seplyarskiy AU - Wendy S.W. Wong AU - Thierry Vilboux AU - Dale L. Bodian AU - Benjamin D. Solomon AU - Joris A. Veltman AU - John F. Deeken AU - Christian Gilissen AU - John E. Niederhuber TI - Germline <em>de novo</em> mutation clusters arise during oocyte aging in genomic regions with increased double-strand break incidence AID - 10.1101/140111 DP - 2017 Jan 01 TA - bioRxiv PG - 140111 4099 - http://biorxiv.org/content/early/2017/06/30/140111.short 4100 - http://biorxiv.org/content/early/2017/06/30/140111.full 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&gt;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.