Diet-induced hypermethylation at agouti viable yellow is not inherited transgenerationally through the female

A^vy locus in mice displays phenotypes ranging from yellow (hypomethylated A^vy) to brown (pseudoagouti, hypermethylated A^vy), and the coat color of A^vy/a mice resembles that of their A^vy/a dams, due to epigenetic inheritance. Besides, A^vy can be influenced by environment during embryonary stages -specifically, diet. Both epigenetic inheritance and environmental influence could account for a transgenerational epigenetic effect, and Cropley et al. recently reported evidence for this. Here, however, Waterland et al. said that the findings by Cropley et al. demonstrate only that maternal methyl supplementation helps to prevent the loss of DNA methylation but not prove the transgenerational inheritance of acquired characters.

[...Our] study had two potential outcomes. If the effects of maternal diet on offspring A^vy methylation are partially transmitted to the next generation, we would expect the difference in coat color between the two diet groups to increase with successive generations. If, on the other hand, the effects of methyl supplementation on A^vy methylation are not transmitted transgenerationally, we would expect the coat color difference between the two diet groups to be stable across the three generations. Our findings are clearly consistent with the latter.

As their results are in contradiction with those of Cropley et al., authors suggested that the observed differences could be due mainly for two parameters in the study design: the initial epigenetic state of the A^vy allele (pseudoagouti -hypermethylated A^vy- in the Cropley et al. experiment, and yellow -hypomethylated A^vy- here); and the diet (Cropley et al. used a 3-fold higher level of methyl donors, which authors said could have introduced a toxicity bias). Finally, authors mentioned that, although CpG methylation appears to play a central role in the phenotypic variation of A^vy, additional mechanisms (like histone modifications, for example) must be identified, to see if this loci follows an epigenetic inheritance.

Waterland, RA. et al. 2007. FASEB J [Epub ahead of print]
epigenetics