Uchimura Arikuni, Higuchi Mayumi, Minakuchi Yohei, Ohno Mizuki, Toyoda Atsushi, Fujiyama Asao, Miura Ikuo, Wakana Shigeharu, Nishino Jo, Yagi Takeshi
KOKORO-Biology Group, Laboratories for Integrated Biology, Graduate School of Frontier Biosciences, Osaka University, Suita 565-0871, Japan;
Comparative Genomics Laboratory, National Institute of Genetics, Mishima 411-8540, Japan;
Genome Res. 2015 Aug;25(8):1125-34. doi: 10.1101/gr.186148.114. Epub 2015 Jun 30.
The germline mutation rate is an important parameter that affects the amount of genetic variation and the rate of evolution. However, neither the rate of germline mutations in laboratory mice nor the biological significance of the mutation rate in mammalian populations is clear. Here we studied genome-wide mutation rates and the long-term effects of mutation accumulation on phenotype in more than 20 generations of wild-type C57BL/6 mice and mutator mice, which have high DNA replication error rates. We estimated the base-substitution mutation rate to be 5.4 × 10(-9) (95% confidence interval = 4.6 × 10(-9)-6.5 × 10(-9)) per nucleotide per generation in C57BL/6 laboratory mice, about half the rate reported in humans. The mutation rate in mutator mice was 17 times that in wild-type mice. Abnormal phenotypes were 4.1-fold more frequent in the mutator lines than in the wild-type lines. After several generations, the mutator mice reproduced at substantially lower rates than the controls, exhibiting low pregnancy rates, lower survival rates, and smaller litter sizes, and many of the breeding lines died out. These results provide fundamental information about mouse genetics and reveal the impact of germline mutation rates on phenotypes in a mammalian population.
种系突变率是一个影响遗传变异量和进化速率的重要参数。然而，实验室小鼠的种系突变率以及哺乳动物群体中突变率的生物学意义都尚不明确。在此，我们研究了超过20代野生型C57BL/6小鼠和具有高DNA复制错误率的突变小鼠的全基因组突变率以及突变积累对表型的长期影响。我们估计C57BL/6实验室小鼠每代每个核苷酸的碱基替换突变率为5.4×10^(-9)（95%置信区间 = 4.6×10^(-9) - 6.5×10^(-9)），约为人类报道速率的一半。突变小鼠的突变率是野生型小鼠的17倍。突变品系中异常表型出现的频率比野生型品系高4.1倍。几代之后，突变小鼠的繁殖率显著低于对照组，表现为低妊娠率、较低的存活率和较小的窝仔数，并且许多繁殖系灭绝。这些结果提供了有关小鼠遗传学的基础信息，并揭示了种系突变率对哺乳动物群体表型的影响。
