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.
Highlights
Spontaneous germline mutations generate genetic diversity in populations of sexually reproductive organisms, and are regarded as a driving force of evolution
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; we concluded that 8-oxoG is a causative molecule for spontaneous and inheritable mutations of the germ lineage cells
Spontaneous mutations increased in Mth12/2/Ogg12/2/Mutyh2/2 (TOY-KO) mice
Summary
Spontaneous germline mutations generate genetic diversity in populations of sexually reproductive organisms, and are regarded as a driving force of evolution. 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. 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; we concluded that 8-oxoG is a causative molecule for spontaneous and inheritable mutations of the germ lineage cells. To evaluate the contribution of 8-oxoG to de novo germline mutation, we established the Mth1/Ogg1/Mutyh triple knockout (TOY-KO) mice, in which unrepaired endogenous 8-oxoG accumulates in the genome DNA. In this paper, using the TOY-KO mice, we showed that 8-oxoG causes G to T mutations in germ lineage cells (Supplementary Fig. S1 online)
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