Genetic and chemotherapeutic influences on germline hypermutation

Mutations in the germline generates all evolutionary genetic variation and is a cause of genetic disease. Parental age is the primary determinant of the number of new germline mutations in an individual's genome(1,2). Here we analysed the genome-wide sequences of 21,879 families with rare genetic diseases and identified 12 individuals with a hypermutated genome with between two and seven times more de novo single-nucleotide variants than expected. In most families (9 out of 12), the excess mutations came from the father. Two families had genetic drivers of germline hypermutation, with fathers carrying damaging genetic variation in DNA-repair genes. For five of the families, paternal exposure to chemotherapeutic agents before conception was probably a key driver of hypermutation. Our results suggest that the germline is well protected from mutagenic effects, hypermutation is rare, the number of excess mutations is relatively modest and most individuals with a hypermutated genome will not have a genetic disease.

Automated summary

Mutations in the germline are the source of all evolutionary genetic variations and can cause genetic diseases. Parental age is the main factor determining the number of new germline mutations in an individual's genome. Through analysis of genome-wide sequences from 21,879 families with rare genetic diseases, it was discovered that 12 individuals had a hypermutated genome with significantly more de novo single-nucleotide variants than expected. In most cases, the excess mutations were derived from the father. Some families had genetic drivers for germline hypermutation, with fathers carrying damaging genetic variations in DNA-repair genes. For five families, paternal exposure to chemotherapeutic agents before conception was likely a key factor for hypermutation. Overall, the results suggest that the germline is well protected from mutagenic effects, hypermutation is rare, and most individuals with a hypermutated genome will not develop genetic diseases.