小鼠作为哺乳动物模型,用于理解新突变的变异性质,一个具有进化和医学意义的问题。先前的研究表明,小鼠的单核苷酸突变(SNM)发生率约为人类的50%。然而,信息主要来自涉及C57BL/6菌株的研究,其他小鼠品系的信息很少。这里,我们研究了在遗传和临床研究中常用的四种近交系的59个小鼠品系中积累的突变(BALB/cAnNRj,C57BL/6JRj,C3H/HeNRj,和FVB/NRj),由兄弟姐妹交配维持8-9代。通过分析Illumina全基因组测序数据,我们估计小鼠新SNM的平均发生率约为μ=6.7×10-9。然而,菌株之间的SNM谱有很大差异,因此,新突变带来的负担也因菌株而异。例如,FVB菌株的频谱明显向C→A变性倾斜,并且可能比其他菌株经历更高的有害负荷,由于谷氨酸密码子中无义突变的频率增加。最后,我们观察到DNA序列环境中新SNM的比率有很大的变化,CpG位点及其邻近核苷酸起着重要的感化。
The mouse serves as a mammalian model for understanding the nature of variation from new mutations, a question that has both evolutionary and medical significance. Previous studies suggest that the rate of single-nucleotide mutations (SNMs) in mice is ∼50% of that in humans. However, information largely comes from studies involving the C57BL/6 strain, and there is little information from other mouse strains. Here, we study the mutations that accumulated in 59 mouse lines derived from four inbred strains that are commonly used in genetics and clinical research (BALB/cAnNRj, C57BL/6JRj, C3H/HeNRj, and FVB/NRj), maintained for eight to nine generations by brother-sister mating. By analyzing Illumina whole-genome sequencing data, we estimate that the average rate of new SNMs in mice is ∼μ = 6.7 × 10-9. However, there is substantial variation in the spectrum of SNMs among strains, so the burden from new mutations also varies among strains. For example, the FVB strain has a spectrum that is markedly skewed toward C→A transversions and is likely to experience a higher deleterious load than other strains, due to an increased frequency of nonsense mutations in glutamic acid codons. Finally, we observe substantial variation in the rate of new SNMs among DNA sequence contexts, CpG sites, and their adjacent nucleotides playing an important role.