Germ cells carry the epigenetic benefits of grandmother's diet

Environmental influences on epigenetics are important for understanding the mechanisms and inheritance of biological variation. Some of the best models for mammalian epigenetics are the yellow alleles of agouti in mice. Alleles such as A ^vy produce readily distinguished agouti, yellow, and mottled coat-color epigenetic phenotypes. Dietary and genetic variations during development affect the epigenetic phenotypes of offspring (1, 2). Little is known regarding the gestational timing of dietary treatments to affect epigenetics. Although the epigenetic phenotype is partially maternally, and grandmaternally, inherited (1, 3, 4), transgenerational effects of grandmaternal diets have not been reported. In this issue of PNAS, Cropley et al. (5) report the effects of specific timing of maternal dietary methyl supplementation on the coat color of offspring. Surprisingly, they find that maternal supplementation only during midgestation substantially affects offspring coat color. Importantly, they also find that this effect is inherited by the next generation, presumably through germ-line modifications during grandmaternal supplementation.

Mice carrying the A ^vy or A ^iapy agouti allele, combined with a null allele (called a), produce a spectrum of epigenetic variation. This spectrum includes coat color, which varies from entirely yellow mice, through an array of mottled varieties, to fully agouti mice (1, 6). Yellow and mottled mice are obese and are prone to diabetes and cancer, in contrast to fully agouti mice, known as pseudoagoutis, which are lean and nondiabetic (7, 8). There is a high correlation between DNA methylation of the A ^vy or A ^iapy alleles and the proportion of agouti in the coats of these mice (2, 4, 6, 9, 10). This spectrum of epigenetic variation is shifted toward agouti (and away from yellow) by maternal dietary methyl supplementation (1, 9, 10).

In gestation, much of the …

*E-mail: cooneycraiga{at}uams.edu