8-oxoguanine causes spontaneous de novo germline mutations in mice

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Cell Lineage
  • DNA Glycosylases / genetics*
  • DNA Repair
  • Genetic Variation
  • Germ-Line Mutation / drug effects*
  • Guanine / analogs & derivatives*
  • Guanine / pharmacology
  • Hydrocephalus / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mutation
  • Mutation Rate
  • Phosphoric Monoester Hydrolases / genetics*
  • Sequence Analysis, DNA

Substances

  • 8-hydroxyguanine
  • Guanine
  • Phosphoric Monoester Hydrolases
  • DNA Glycosylases
  • Ogg1 protein, mouse
  • mutY adenine glycosylase
  • Nudt1 protein, mouse