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Genetic and chemotherapeutic influences on germline hypermutation.

ABSTRACT: 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.

SUBMITTER: Kaplanis J

PROVIDER: S-EPMC9117138 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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Genetic and chemotherapeutic influences on germline hypermutation.

Kaplanis Joanna J Ide Benjamin B Sanghvi Rashesh R Neville Matthew M Danecek Petr P Coorens Tim T Prigmore Elena E Short Patrick P Gallone Giuseppe G McRae Jeremy J Carmichael Jenny J Barnicoat Angela A Firth Helen H O'Brien Patrick P Rahbari Raheleh R Hurles Matthew M

Nature 20220511 7910

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<sup>1,2</sup>. 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 exc ...[more]

PMID: 35545669

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Project description:CPT-11 is a first-line chemotherapeutic agent for the treatment of colorectal cancer in clinic. Previous studies including ours have demonstrated that CPT-11 is, however, toxic to the intestinal epithelium and resident peritoneal macrophages. By interacting with B1 cells, the resident peritoneal macrophages play critical roles in the maintenance of gastrointestinal homeostasis. It remains therefore elusive whether these peritoneal innate immune cells could be rebuilt spontaneously or artificially after being impaired by CPT-11 administration. In this study, we found that mouse resident peritoneal macrophages, namely the large peritoneal macrophages (LPMs) with a CD11b+F4/80hiGATA6+ phenotype, and B1 (CD19+CD23-) cells were depleted by intraperitoneal (i.p.) CPT-11 treatment within 1 week, but reappeared from day 14 after CPT-11 treatment. However, the recovery processes of these innate immune cells were slow, as their counts could not be fully recovered even 2 months later, when compared with that of vehicle-treated control group. Interestingly, in the peritoneal cavity of the mice treated with CPT-11, the cell counts of LPMs and B1 cells were significantly increased after adoptive transfer with syngeneic peritoneal exudate cells (PECs) from healthy mice. Adoptive transfer with bone marrow cells also slightly increased, although not significantly, the cell counts of LPMs and B1 cells in CPT-11-treated mice. The survival rate of bacterial infected mice was significantly reduced by i.p. CPT-11 treatment in comparison with vehicle-treated or untreated control groups. Besides, oral administration of CPT-11 also had a delayed toxicity on the resident peritoneal macrophages. Our results suggest that CPT-11 has prolonged deleterious effects on peritoneal innate immune cells but adoptive transfer with PECs may accelerate their recovery processes, highlighting the potential of adoptive cell transfer as an avenue to counteract the adverse effects of this chemotherapeutic agent.

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Genetic and chemotherapeutic influences on germline hypermutation.

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Genetic and chemotherapeutic influences on germline hypermutation.

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