Among genetically identical 'agouti viable yellow' (Avy) mice, some exhibit differences in color and weight due to epigenetics. This system involves molecular tags added to DNA during development, affecting gene expression. A 2003 study found that supplementing female mice's diets with 'methyl donor' nutrients before and during pregnancy influenced the characteristics of their Avy offspring.
The Avy gene is classified as a 'metastable epiallele,' with its DNA methylation level established randomly in early embryonic development. The study suggested metastable epialleles might explain variations among inbred mice, such as weight gain on high-fat diets. However, the prevalence of these epialleles remained unknown for over two decades.
A recent study led by Dr. Robert A. Waterland at Baylor College of Medicine reveals that metastable epialleles are rare in mice. Published in Nucleic Acids Research, the research involved scanning for systemic interindividual variation in DNA methylation across the mouse genome.
“We performed a comprehensive, unbiased scan of epigenetic variation across the entire mouse genome, analyzing DNA methylation patterns in three different tissues – liver, kidney and brain – from each of ten genetically identical mice,” said co-first author Dr. Chathura J. Gunasekara.
“Out of millions of potential sites, we found only 29 metastable epialleles,” he added.
Co-first author Uditha Maduranga noted another finding: “Another surprising finding was that maternal diet – specifically, supplementation with pro-methylation nutrients like folate and vitamin B12 – had no effect on the methylation of the newly-discovered metastable epialleles.”
Dr. Waterland explained how previous discoveries motivated further research: “The discovery of the dietary supplementation effect in Avy mice 20 years ago motivated us to search for metastable epialleles in humans.”
This effort led to identifying thousands of human genomic regions called CoRSIVs which are sensitive to early embryonic environments and implicated in diseases.
“Rather than the inbred mice used in biomedical research for decades,” Waterland continues, “our results indicate that outbred mice are likely a better model to understand how nutrition during development affects interindividual epigenetic variation in humans.”
Taylor Zhang, Jonathan N. Wells, Maria S. Baker, Eleonora Laritsky, Yumei Li, Cristian Coarfa and Yi Zhu also contributed to this work from institutions including Baylor College of Medicine.
Funding came from NIH/NIDDK (1R01DK125562), USDA/ARS (CRIS 3092-5-001-059), NIH R35-GM122550 among others.
