Germline mutation rates and the long-term phenotypic effects of mutation accumulation in wild-type laboratory mice and mutator mice.
Germline mutation rates and the long-term phenotypic effects of mutation accumulation in wild-type laboratory mice and mutator mice.
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DOI：
10.1101/gr.186148.114
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发表时间：
2015-08
期刊：
影响因子：
7
通讯作者：
Yagi T
中科院分区：
文献类型：
--
作者：
Uchimura A;Higuchi M;Minakuchi Y;Ohno M;Toyoda A;Fujiyama A;Miura I;Wakana S;Nishino J;Yagi T
种系突变率是影响遗传变异量和进化速度的重要参数。然而，无论是实验室小鼠的生殖系突变率，还是哺乳动物种群中突变率的生物学意义都不清楚。在这里，我们研究了DNA复制错误率较高的20多代野生型C57BL/6小鼠和突变小鼠的全基因组突变率和突变累积对表型的长期影响。我们估计C57BL/6实验小鼠的碱基替换突变率为每代5.4×10−9(95%可信区间=4.6×10−9-6.5×10−9)，约为人类的一半。突变小鼠的突变率是野生型小鼠的17倍。突变体系的异常表型频率是野生型系的4.1倍。经过几代后，突变鼠的繁殖率大大低于对照组，表现出低怀孕率、低存活率和更小的窝仔数量，许多繁育系灭绝。这些结果提供了关于小鼠遗传学的基本信息，并揭示了生殖系突变率对哺乳动物种群表型的影响。
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.