A natural mutator allele shapes mutation spectrum variation in mice.-猫眼课题宝

DOI：

10.1038/s41586-022-04701-5

发表时间：

2022-05

期刊：

Nature

影响因子：

64.8

通讯作者：

中科院分区：

综合性期刊1区

文献类型：

作者：

来源链接：

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9272728/

虽然种系突变率和谱可以在物种内和物种之间变化，但突变率的常见遗传修饰剂尚未在自然界中确定。在这里，我们使用一个独特的强大的资源搜索基因座，影响种系诱变：一组重组近交系小鼠品系称为BXD，从实验室菌株C57 BL/6 J（B单倍型）和DBA/2 J（D单倍型）的后裔。在几乎不存在自然选择的情况下，每个BXD谱系通过兄弟姐妹交配得以维持，在已知的遗传背景上积累了长达50年的从头突变，该遗传背景是B和D单倍型的独特线性嵌合体。我们发现，在4号染色体上的数量性状基因座上遗传D单倍型的小鼠比遗传B单倍型的小鼠以高50%的速率积累C>A种系突变，这主要是由于被称为SBS 18的C> A主导的突变特征的活性。B和D数量性状基因座单倍型编码Mutyh的不同等位基因，Mutyh是一种DNA修复基因，是导致具有高SBS 18突变负荷的结直肠肿瘤的遗传性癌症易感综合征的基础。B和D Mutyh等位基因都存在于野生种群的小家鼠，提供的证据表明，共同的遗传变异调节种系突变的模式哺乳动物物种。

Although germline mutation rates and spectra can vary within and between species, common genetic modifiers of the mutation rate have not been identified in nature. Here we searched for loci that influence germline mutagenesis using a uniquely powerful resource: a panel of recombinant inbred mouse lines known as the BXD, descended from the laboratory strains C57BL/6J (B haplotype) and DBA/2J (D haplotype). Each BXD lineage has been maintained by brother–sister mating in the near absence of natural selection, accumulating de novo mutations for up to 50 years on a known genetic background that is a unique linear mosaic of B and D haplotypes. We show that mice inheriting D haplotypes at a quantitative trait locus on chromosome 4 accumulate C>A germline mutations at a 50% higher rate than those inheriting B haplotypes, primarily owing to the activity of a C>A-dominated mutational signature known as SBS18. The B and D quantitative trait locus haplotypes encode different alleles of Mutyh, a DNA repair gene that underlies the heritable cancer predisposition syndrome that causes colorectal tumors with a high SBS18 mutation load. Both B and D Mutyh alleles are present in wild populations of Mus musculus domesticus, providing evidence that common genetic variation modulates germline mutagenesis in a model mammalian species.