Significant Strain Variation in the Mutation Spectra of Inbred Laboratory Mice
Significant Strain Variation in the Mutation Spectra of Inbred Laboratory Mice
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DOI：
10.1093/molbev/msz026
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发表时间：
2019-05-01
影响因子：
10.7
通讯作者：
Dumont, Beth L.
中科院分区：
文献类型：
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作者：
Dumont, Beth L.
突变提供了种群中所有新等位基因的最终来源，包括导致疾病和燃料适应的变异。最近的全基因组测序研究揭示了个体间突变率的变化和群体间特定核苷酸变化（突变谱）相对频率的差异。虽然父母年龄是个体间总体突变率差异的主要驱动因素，但突变谱变异的原因仍不太清楚。在这里，我使用29个近交系实验室小鼠品系的高质量全基因组序列来探索突变谱中品系变异的根本原因。我的分析利用了近交系小鼠品系之间遗传相关性的独特马赛克模式，以识别多个品系之间共享的单倍型上的品系私有变体，因为它们最近来自共同祖先。我发现，这些菌株的私人等位基因是强烈富集最近的从头突变，缺乏广泛的净化选择的信号，这表明他们忠实地重演了自发突变景观在单一菌株。在标准化实验室条件下饲养的近交系小鼠品系中，品系私有变异体的谱变化很大。这种变异不仅仅是由繁殖年龄的菌株差异来解释的，这提高了分离遗传差异影响给定菌株中出现的新突变的可能性。总的来说，这些发现意味着非常精确的核苷酸特异性遗传机制的作用，以调整哺乳动物的从头突变景观，并强调突变率控制的遗传复杂性。
Mutation provides the ultimate source of all new alleles in populations, including variants that cause disease and fuel adaptation. Recent whole genome sequencing studies have uncovered variation in the mutation rate among individuals and differences in the relative frequency of specific nucleotide changes (the mutation spectrum) between populations. Although parental age is a major driver of differences in overall mutation rate among individuals, the causes of variation in the mutation spectrum remain less well understood. Here, I use high-quality whole genome sequences from 29 inbred laboratory mouse strains to explore the root causes of strain variation in the mutation spectrum. My analysis leverages the unique, mosaic patterns of genetic relatedness among inbredmouse strains to identify strain private variants residing on haplotypes shared between multiple strains due to their recent descent from a common ancestor. I show that these strain-private alleles are strongly enriched for recent de novo mutations and lack signals of widespread purifying selection, suggesting their faithful recapitulation of the spontaneous mutation landscape in single strains. The spectrum of strain-private variants varies significantly among inbred mouse strains reared under standardized laboratory conditions. This variation is not solely explained by strain differences in age at reproduction, raising the possibility that segregating genetic differences affect the constellation of new mutations that arise in a given strain. Collectively, these findings imply the action of remarkably precise nucleotide-specific genetic mechanisms for tuning the de novo mutation landscape in mammals and underscore the genetic complexity of mutation rate control.