Graduate School of Frontier Biosciences, Osaka University


Mouse Evolution Project reveals germline mutation rates and the long-term phenotypic effects of mutation accumulation

Journal Genome Res 25, 1125-1134 (2015)
Authors Uchimura A. (1), Higuchi M. (1), Minakuchi Y. (2), Ohno M. (3), Toyoda A. (2), Fujiyama A. (2), Miura I. (4), Wakana S. (4), Nishino J. (5), Yagi T. (1)

  1. KOKORO-Biology Group, Laboratories for Integrated Biology, Graduate School of Frontier Biosciences, Osaka University, Suita 565-0871, Japan
  2. Comparative Genomics Laboratory, National Institute of Genetics, Mishima 411-8540, Japan
  3. Department of Medical Biophysics and Radiation Biology, Faculty of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
  4. Technology and Development Team for Mouse Phenotype Analysis, Japan Mouse Clinic, RIKEN BioResource Center, Tsukuba 305-0074, Japan
  5. Department of Biostatistics, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
Title Germline mutation rates and the long-term phenotypic effects of mutation accumulation in wild-type laboratory mice and mutator mice
PubMed 26129709
Laboratory KOKORO-Biology Group 〈Prof. Yagi〉

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 their long-term effects on phenotype in more than 20 generations (9 years of breeding) 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. There were many kinds of phenotypes, including morphological phenotypes, disease phenotypes and behavioral phenotypes such as “human audible vocalizer mice.” Mutator lines had also diverse quantitative traits after several generations. In addition, 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.

Fig. 1. Strategy of the present study.
The breeding of mutator mice that have an increased spontaneous germline mutation rate provides an efficient experimental model with which to study the expression of genetic variation and its maintenance in a population. Illustrations of mice were kindly provided by Dr. Masuya (RIKEN BRC, Japan).


Fig. 2. Phenotypic anomalies observed in mutator mouse lines. (A)-(F)
Photographs of typical, frequently observed anomalies, including (A) minor color, (B) hydrocephaly, (C) closed eye, (D) cut tail, (E) tail kink, (F) cataract. (G)-(K) Inherited anomalies, including (G) syndactyly (right photograph shows a normal paw), (H) priapism, (I), short limbs and tail (right photograph shows a normal mouse), (J) color dilution (left), and (K) a human-audible vocalizer.


Fig. 3. Relationship between 8-week-old male body weight (A) or live offspring per mating (B) and generation number (red: mutator; blue: control).
Dots: individual mice; circles, mean for the generation. Solid line: simple linear regression of the posterior means. Green line: regression curve using the recessive lethal mutation model for the mutator lines.


Table 1. Mammalian mutation rates and their effects on survival
Red colored rows are presented in this study.