Germline De Novo Mutations with parent of origin in WGS trios. Germline De Novo Mutations with parent of origin in WGS trios

Clustering of mutations has been observed in cancer genomes as well as for de novo mutations (DNMs) in the germline. We identified 1,796 clustered DNMs (cDNMs) within whole-genome sequencing data from 1,291 parent-offspring trios to investigate their patterns and inferred a mutational mechanism. We found that the number of clusters on the maternal allele was positively correlated with maternal age and that these consist of more individual mutations with larger inter-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 transversions. Finally, we found that maternal clusters associate with processes involving double-stranded-breaks (DSBs) such as meiotic gene conversions and de novo deletion events. These findings suggest accumulation... (for more see dbGaP study page.)