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Germline De Novo Mutation Clusters Arise During Oocyte Aging In Genomic Regions With Increased Double-Strand Break Incidence

By Jakob M. Goldmann, Vladimir B. Seplyarskiy, Wendy S.W. Wong, Thierry Vilboux, Dale L. Bodian, Benjamin D. Solomon, Joris A. Veltman, John F. Deeken, Christian Gilissen, John E. Niederhuber

Posted 27 May 2017
bioRxiv DOI: 10.1101/140111 (published DOI: 10.1038/s41588-018-0071-6)

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 was positively correlated only with maternal age and that maternal clusters consist of more individual mutations with larger intra-mutational distances compared to paternal clusters. Maternal clusters were enriched at specific loci on chromosomes 8, 9 and 16 in regions with increased maternal mutation rate. Moreover, 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, de novo deletions events and recombination. These findings suggest accumulation of DSB-induced mutations throughout oocyte aging as an underlying mechanism leading to maternal mutation clusters.

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