16.4 EPIGENETICS AND ENVIRONMENTAL AGENTS 401 Promoter within Transposable element transposable Normal promoter element for Agouti gene Slightly mottled Yellow Mottled Heavily mottled Pseudo- Agouti gene agouti (b) Range in coat-color phenotypes in Ava mice due to eplgenetic changes (a) The Insertion of a transposable element to create the Ay allele 50- 100- Supplemented diet 90어 Normal diet 40- 80- 70- 30- 60- 50- 20- 40- 30어 10- 20- 10- 0- Yellow SlightlyMottled Heavily Pseudo- 0+ Yellow SlightlyMottled Heavily Pseudo- mottled mottled mottled mottled agouti mobe (c) Effect of diet on coat color (d) Level of DNA methylation of CpG Islands within the TE among mice with different coat colors FIGUR E 16 8 Dietury offerts on mat olor in mice (y) •designated 4 is cuused by the insertio mutution TE unstrum AWa offspring (% of total) % methylationof CpG islands within the transposable element FIGURE 16.8 Dietary effects on coat color in mice. (a) A mutation in the Agouti gene, designated A", is caused by the insertion of a TE upstream from the normal Agouti promoter. The TE promoter is very active and causes the overexpression of the Agouti gene. (b) Mice carrying the A" allele exhibit a range of phenotypes. The mice shown here are heterozygotes, A"a; they carry the mutant A" alele and a loss-of-function allele (a). (c) Effects of diet supple- mentation on coat color. White bars represent offspring from females given a normal diet, and black bars represent offspring from females given a supplemented diet. (d) DNA methylation patterns among mice with different coat colors. The samples to determine DNA methylation were obtained from cells in the tail. (a).(e),(d) Source: Data from R. A. Waterland and R. L. Jirtle (2003) Transposable Elements: Targets for Early Nutritional Effects on Epigenetic Gene Regulation. Mol. Cell. Biol. 23, 5293- 5300. (b) From: D.C. Dolinoy et al., "Maternal genistein alters coat color and protects Avy mouse offspring from obesity by modifying the fetal epigenome," Environ Health Perspect. 2006 Apr, 114(4): 567-572. Reproduced with permission Genes-Traits The mice shown in part (b) are genetically identical. Their differences in coat color are due to epigenetic modifications that occur during early stages of development.