Genetic and chemotherapeutic influences on germline hypermutation.
Genetic and chemotherapeutic influences on germline hypermutation.
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DOI：
10.1038/s41586-022-04712-2
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发表时间：
2022-05
期刊：
影响因子：
64.8
通讯作者：
中科院分区：
文献类型：
--
作者：
生殖系的突变产生了所有进化的遗传变异，是遗传病的原因之一。父母的年龄是个体基因组中新的生殖系突变数量的主要决定因素。在这里，我们分析了21,879个患有罕见遗传病的家庭的全基因组序列，并确定了12个基因组高度突变的个体，其从头开始的单核苷酸变异比预期多2到7倍。在大多数家庭中(12个家庭中有9个)，多余的突变来自父亲。有两个家庭有生殖系超突变的遗传驱动因素，父亲在DNA修复基因中携带破坏性的遗传变异。对于其中五个家庭来说，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。我们的结果表明，生殖系受到很好的保护，不受诱变效应的影响，超突变很少见，过度突变的数量相对较少，大多数拥有超突变基因组的个体不会患上遗传病。一项对21,879个患有罕见遗传病的家庭的研究发现，12个家庭的胚系突变超过2-7倍，其中大部分是由于DNA修复缺陷或暴露在诱变化疗中，尽管大多数基因组高度突变的人不会患上遗传病。
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. A study of 21,879 families with rare genetic diseases identifies 12 with 2- to 7-fold excess of germline mutations, most of which are due to DNA repair defects or exposure to mutagenic chemotherapy, although most individuals with a hypermutated genome will not have a genetic disease.
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DOI：
10.1001/jama.2018.6228
发表时间：
2018-06-19
期刊：
JAMA
影响因子：
--
作者：
Hu C;Hart SN;Polley EC;Gnanaolivu R;Shimelis H;Lee KY;Lilyquist J;Na J;Moore R;Antwi SO;Bamlet WR;Chaffee KG;DiCarlo J;Wu Z;Samara R;Kasi PM;McWilliams RR;Petersen GM;Couch FJ
通讯作者：
Couch FJ
影响因子：
7
作者：
Boot A;Huang MN;Ng AWT;Ho SC;Lim JQ;Kawakami Y;Chayama K;Teh BT;Nakagawa H;Rozen SG
通讯作者：
Rozen SG
影响因子：
7
作者：
Jager, Myrthe;Blokzijl, Francis;Cuppen, Edwin
通讯作者：
Cuppen, Edwin
影响因子：
16.6
作者：
Adewoye, Adeolu B.;Lindsay, Sarah J.;Dubrova, Yuri E.;Hurles, Matthew E.
通讯作者：
Hurles, Matthew E.
DOI：
10.1073/pnas.1418652112
发表时间：
2015-03-17
影响因子：
11.1
作者：
Harris, Kelley
通讯作者：
Harris, Kelley