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Sci Rep. 2014 Apr 15;4:4689. doi: 10.1038/srep04689.

8-oxoguanine causes spontaneous de novo germline mutations in mice.

Author information

1
Department of Medical Biophysics and Radiation Biology, Faculty of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
2
1] Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan [2] Research Center for Nucleotide Pool, Kyushu University, Fukuoka 812-8582, Japan.
3
Mutagenesis and Genomics Team, RIKEN BioResource Center, Tsukuba 305-0074, Japan.
4
Radioisotope Center, Kyushu University, Fukuoka 812-8582, Japan.
5
1] Department of Computer Bioscience, Nagahama Institute of Bio-Science and Technology, Nagahama 526-0829, Japan [2] Research Fellow of the Japan Society for the Promotion of Science.
6
Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.
7
Department of Computer Bioscience, Nagahama Institute of Bio-Science and Technology, Nagahama 526-0829, Japan.

Abstract

Spontaneous germline mutations generate genetic diversity in populations of sexually reproductive organisms, and are thus regarded as a driving force of evolution. However, the cause and mechanism remain unclear. 8-oxoguanine (8-oxoG) is a candidate molecule that causes germline mutations, because it makes DNA more prone to mutation and is constantly generated by reactive oxygen species in vivo. We show here that endogenous 8-oxoG caused de novo spontaneous and heritable G to T mutations in mice, which occurred at different stages in the germ cell lineage and were distributed throughout the chromosomes. Using exome analyses covering 40.9 Mb of mouse transcribed regions, we found increased frequencies of G to T mutations at a rate of 2 × 10(-7) mutations/base/generation in offspring of Mth1/Ogg1/Mutyh triple knockout (TOY-KO) mice, which accumulate 8-oxoG in the nuclear DNA of gonadal cells. The roles of MTH1, OGG1, and MUTYH are specific for the prevention of 8-oxoG-induced mutation, and 99% of the mutations observed in TOY-KO mice were G to T transversions caused by 8-oxoG; therefore, we concluded that 8-oxoG is a causative molecule for spontaneous and inheritable mutations of the germ lineage cells.

PMID:
24732879
PMCID:
PMC3986730
DOI:
10.1038/srep04689
[Indexed for MEDLINE]
Free PMC Article

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