Genetic and chemotherapeutic causes of germline hypermutation

Abstract

Mutation in the germline is the source of all evolutionary genetic variation and a cause of genetic disease. Previous studies have shown parental age to be the primary determinant of the number of new germline mutations seen in an individual's genome. Here we analysed the genome-wide sequences of 21,879 families with rare genetic diseases and identified 12 hypermutated individuals with between two and seven times more de novo single nucleotide variants (dnSNVs) than expected. In most of these families (9/12) the excess mutations could be attributed to the father. We determined that two of these families had genetic drivers of germline hypermutation, with the fathers carrying damaging genetic variation in known DNA repair genes, causing distinctive mutational signatures. For five families, by analysing clinical records and mutational signatures, we determined that paternal exposure to chemotherapeutic agents prior to conception was a key driver of hypermutation. Our results suggest that the germline is well protected from mutagenic effects, hypermutation is rare and relatively modest in degree and that most hypermutated individuals will not have a genetic disease.

Chemotherapy Signatures Map Evolution of Therapy-Related Myeloid Neoplasms

“…Though 5-Fluorouracil is known to leave a distinct SBS signature (SBS17a), no evidence of it was seen in this cohort, in line with its mechanism of mutagenicity on dividing – and not quiescent – cells 12 . Conversely, adducts generated by melphalan-and platinum-based agents are not dependent on cell turnover 9, 12 and induce mutagenesis in tumor and normal tissues 19, 20 . In fact, the mutational burden between de novo AML and tMN without melphalan or platinum exposure were strikingly similar (Wilcoxon test, p = 0.587; Fig 1e ), adding evidence that chemotherapies typically associated with tMN may facilitate malignancy in absence of any appreciable increase in SBS mutagenesis 12 .…”

“…Chemotherapy-related mutational signatures are only detectable in bulk WGS following the clonal expansion of a single cell bearing its unique catalogue of chemotherapy-induced mutations (i.e., the single-cell expansion model, Fig 1a ). The resultant mutational signature thus serves as a genomic single-cell barcode, linked to a discrete clinical and temporal exposure 6-9, 11, 21 . Here, we leverage chemotherapy-induced mutational signatures to measure genomic evolution of tMN with reference to each patient’s known therapeutic history.…”

“…Preleukemic clones (i.e., clonal hematopoiesis) are detectable years before the development of these aggressive malignancies [3][4][5] , though the genomic events leading to transformation and expansion are not well-defined. Here, leveraging distinctive chemotherapy-associated mutational signatures [6][7][8][9][10][11][12] from whole-genome sequencing data and targeted sequencing of pre-chemotherapy samples, we reconstruct the evolutionary life-history of 39 therapy-related myeloid malignancies. A dichotomy is revealed, in which neoplasms with evidence of chemotherapy-induced mutagenesis from platinum and melphalan are relatively hypermutated and enriched for complex structural variants (i.e., chromothripsis), while neoplasms with alternative exposures bear a similar profile to de novo acute myeloid leukemia.…”

Nature of spontaneously arising single base substitutions in normal cells

“…In a recently reported cohort study (Kaplanis et al, 2021), 12 hypermutated individuals were identified from over 20,000 parent offspring sequenced trios, with a two to sevenfold increase in the number of de novo single nucleotide variants (SNVs) in the genome. Both genetic and environmental exposures (e.g.…”

“…They found germline mutation rates were increased by the defects in DNA repair genes, XPC and MPG were identified from paternal mutator variants in the study. However, defects in DNA repair pathways do not always behave similarly in the soma and the germline, they found somatic mutator gene MBD4 did not have a detectable effect in the germline ( (Kaplanis et al, 2021).…”