Niederhuber, J. E. | Search bioRxiv

bioRxiv2017

Mendelian inheritance errors in whole genome sequenced trios are enriched in repeats and cluster within copy number losses

Trio-based whole genome sequencing (WGS) data can contribute significantly towards the development of quality control methods that can be applied to non-family WGS. Mendelian inheritance errors (MIEs) in parent-offspring trios are commonly attributed to erroneous sequencing calls, as the rate of true de novo mutations is extremely low compared to the incidence of MIEs. Here, we analyzed WGS data from 1,314 trios across diverse human populations with the goal of studying the characteristics of MIEs. We applied filters based on genotype call quality and observed that filtering has a greater impact on frequent MIEs. Our results indicate that MIEs are enriched in repeats and MIE density correlates with short interspersed nuclear elements (SINEs) density. We also observed clustered MIEs in regions overlapping large deletions. We created population-specific MIE profiles and discovered regions that represent different MIE distributions across populations. Finally, we have provided population-specific MIE tracks that can be loaded in UCSC Genome Browser. These profiles can be used for flagging calls in proximity of clustered MIEs before allele frequency and admixture calculations, annotating candidate de novo mutations, discovering population-specific putative deletions, and for distinguishing between regions that have errors due to sequence quality vs. chromosomal anomalies.

genomics↗

bioRxiv2017

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

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.

genomics↗