No evidence for cumulative effects in a Dnmt3b hypomorph across multiple generations

Neil A. Youngson, Trevor Epp, Amity R. Roberts, Lucia Daxinger, Alyson Ashe, Edward Huang, Krystal L. Lester, Sarah K. Harten, Graham F. Kay, Timothy Cox, Jacqueline M. Matthews, Suyinn Chong, Emma Whitelaw

Observations of inherited phenotypes that cannot be explained solely through genetic inheritance are increasing. Evidence points to transmission of non-DNA molecules in the gamete as mediators of the phenotypes. However, in most cases it is unclear what the molecules are, with DNA methylation, chromatin proteins, and small RNAs being the most prominent candidates. From a screen to generate novel mouse mutants of genes involved in epigenetic reprogramming, we produced a DNA methyltransferase 3b allele that is missing exon 13. Mice that are homozygous for the mutant allele have smaller stature and reduced viability, with particularly high levels of female post-natal death. Reduced DNA methylation was also detected at telocentric repeats and the X-linked Hprt gene. However, none of the abnormal phenotypes or DNA methylation changes worsened with multiple generations of homozygous mutant inbreeding. This suggests that in our model the abnormalities are reset each generation and the processes of transgenerational epigenetic reprogramming are effective in preventing their inheritance.