title: 8-oxoguanine causes spontaneous de novo germline mutations in mice.
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.
authors.affiliation: Department of Medical Biophysics and Radiation Biology, Faculty of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Mizuki
authors.initials: M
authors.lastname: Ohno
authors.affiliation: 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.
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Sakumi
authors.affiliation: Mutagenesis and Genomics Team, RIKEN BioResource Center, Tsukuba 305-0074, Japan.
authors.forename: Ryutaro
authors.initials: R
authors.lastname: Fukumura
authors.affiliation: Radioisotope Center, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Furuichi
authors.affiliation: 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.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Iwasaki
authors.affiliation: Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Hokama
authors.affiliation: Department of Computer Bioscience, Nagahama Institute of Bio-Science and Technology, Nagahama 526-0829, Japan.
authors.forename: Toshimichi
authors.initials: T
authors.lastname: Ikemura
authors.affiliation: Department of Medical Biophysics and Radiation Biology, Faculty of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Teruhisa
authors.initials: T
authors.lastname: Tsuzuki
authors.affiliation: Mutagenesis and Genomics Team, RIKEN BioResource Center, Tsukuba 305-0074, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Gondo
authors.affiliation: 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.
authors.forename: Yusaku
authors.initials: Y
authors.lastname: Nakabeppu
mesh_terms: D000818:Animals; D001483:Base Sequence; D019070:Cell Lineage; D045647:DNA Glycosylases / Q000235:genetics*; D004260:DNA Repair; D014644:Genetic Variation; D018095:Germ-Line Mutation / Q000187:drug effects*; D006147:Guanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006849:Hydrocephalus / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D059645:Mutation Rate; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: C024829:8-hydroxyguanine; D006147:Guanine; D010744:Phosphoric Monoester Hydrolases; D045647:DNA Glycosylases; C485990:Ogg1 protein, mouse; C061738:mutY adenine glycosylase; C509779:Nudt1 protein, mouse
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