Next Generation Sequencing evaluation and mutation signature analyses of de novo single nucleotide variants from multi-child human families

We used whole genome sequencing of multi-child human families and mutational signature analyses to elucidate the mechanisms involved in the genesis of germline de novo single nucleotide variants (SVNs). We show that SNVs increase with paternal age particularly at CpG sites and that there was significant interfamily variability in the yearly rate of increase. Signature analyses suggest that accumulation of endogenous and exogenous DNA damage and inaccurate DNA mismatch repair mechanisms are sources of human germline SNVs as function of paternal age. Our findings provide important information for understanding the potential causes of human germline SNVs and suggest that variation in these processes contribute to the extensive interfamily variability of the paternal age effect.