Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.
Department of Biological Chemistry, University of Michigan, Ann Arbor, MI, USA.
Nature. 2022 May;605(7910):503-508. doi: 10.1038/s41586-022-04712-2. Epub 2022 May 11.
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. 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.
胚系突变产生了所有进化遗传变异，也是遗传疾病的一个原因。父母年龄是个体基因组中新的胚系突变数量的主要决定因素。在这里，我们分析了 21879 个患有罕见遗传疾病的家庭的全基因组序列，鉴定出 12 名个体的基因组发生了超突变，与预期相比，单核苷酸变异的数量增加了两到七倍。在大多数家庭（12 个家庭中的 9 个）中，多余的突变来自父亲。两个家庭存在胚系超突变的遗传驱动因素，其父亲携带 DNA 修复基因的有害遗传变异。对于其中 5 个家庭，父亲在受孕前接触化疗药物可能是超突变的关键驱动因素。我们的研究结果表明，生殖细胞受到很好的保护，免受诱变效应的影响，超突变很少见，多余突变的数量相对适中，大多数具有超突变基因组的个体不会患有遗传疾病。
