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英国威康桑格研究所Matthew Hurles团队揭示遗传和化疗对种系超突变的影响。该项研究成果于2022年5月11日在线发表在《自然》杂志上。

研究人员分析了21,879个患有罕见遗传病的家庭的全基因组序列，发现有12个个体的基因组突变率过高，新的单核苷酸变体比预期的多2至7倍。在大多数家庭中（12个家庭中的9个），多余的突变来自于父亲。两个家庭有生殖系超突变的遗传驱动因素，父亲携带着DNA修复基因的破坏性遗传变异。对于其中5个家庭来说，父亲在受孕前暴露于化疗药物可能是超突变的一个关键驱动因素。这些结果表明，生殖系统受到很好的保护，不受诱变作用的影响，超突变很罕见，超突变的数量相对不大，大多数基因组超突变的个体不会有遗传病。

据悉，种系突变产生了所有进化的遗传变异，是遗传病的原因之一。父母的年龄是决定个体基因组中新的种系突变数量的主要因素。

附：英文原文

Title: Genetic and chemotherapeutic influences on germline hypermutation

Author: Kaplanis, Joanna, Ide, Benjamin, Sanghvi, Rashesh, Neville, Matthew, Danecek, Petr, Coorens, Tim, Prigmore, Elena, Short, Patrick, Gallone, Giuseppe, McRae, Jeremy, Carmichael, Jenny, Barnicoat, Angela, Firth, Helen, OBrien, Patrick, Rahbari, Raheleh, Hurles, Matthew

Issue&Volume: 2022-05-11

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 genome1,2. 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.

DOI: 10.1038/s41586-022-04712-2

Source: https://www.nature.com/articles/s41586-022-04712-2

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html