Season of conception in rural Gambia affects DNA methylation at putative human metastable epialleles

Authors: WATERLAND, ROBERT - Children'S Nutrition Research Center (CNRC); KELLERMAYER, RICHARD - Baylor College Of Medicine; LARITSKY, ELEONORA - Children'S Nutrition Research Center (CNRC); RAYCO-SOLON, PURA - London School Of Hygeine; HARRIS, RICHARD - Baylor College Of Medicine; TRAVISANO, MICHAEL - University Of Minnesota; ZHANG, WENJUAN - Children'S Nutrition Research Center (CNRC); TORSKAYA, MARIA - Children'S Nutrition Research Center (CNRC); ZHANG, JIEXIN - Md Anderson Cancer Center; SHEN, LANLAN - Children'S Nutrition Research Center (CNRC); MANARY, MARK - Children'S Nutrition Research Center (CNRC); PRENTICE, ANDREW - London School Of Hygeine

Submitted to: PLoS Genetics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/18/2010
Publication Date: 12/23/2010
Citation: Waterland, R.A., Kellermayer, R., Laritsky, E., Rayco-Solon, P., Harris, R.A., Travisano, M., Zhang, W., Torskaya, M.S., Zhang, J., Shen, L., Manary, M.J., Prentice, A.M. 2010. Season of conception in rural Gambia affects DNA methylation at putative human metastable epialleles. PLoS Genetics. 6(12):e1001252.

Interpretive Summary: Studies in mice have shown that in certain sensitive regions of the genome, maternal nutrition before and during pregnancy can affect the establishment of epigenetic mechanisms in her offspring. (Epigenetic mechanisms are gene regulatory mechanisms that are layered on top of the DNA sequence information and, like DNA sequence, are copied and maintained as cells in the body divide and replenish themselves throughout life.) The genomic regions that demonstrate this sensitivity to maternal nutrition are called metastable epialleles. Metastable epialleles have not previously been identified in humans. We used an innovative two-tissue screen for interindividual variation in DNA methylation (an epigenetic mark), and identified putative metastable epialleles in the human genome. Further, we showed that, as with metastable epialleles in mice, epigenetic regulation at these loci is permanently affected by maternal environment around the time of conception. Our results have important implications for understanding how maternal nutrition during pregnancy can affect the health of her baby throughout life.

Technical Abstract: Throughout most of the mammalian genome, genetically regulated developmental programming establishes diverse yet predictable epigenetic states across differentiated cells and tissues. At metastable epialleles (MEs), conversely, epigenotype is established stochastically in the early embryo then maintained in differentiated lineages, resulting in dramatic and systemic interindividual variation in epigenetic regulation. In the mouse, maternal nutrition affects this process, with permanent phenotypic consequences for the offspring. MEs have not previously been identified in humans. Here, using an innovative 2-tissue parallel epigenomic screen, we identified putative MEs in the human genome. In autopsy samples, we showed that DNA methylation at these loci is highly correlated across tissues representing all 3 embryonic germ layer lineages. Monozygotic twin pairs exhibited substantial discordance in DNA methylation at these loci, suggesting that their epigenetic state is established stochastically. We then tested for persistent epigenetic effects of periconceptional nutrition in rural Gambians, who experience dramatic seasonal fluctuations in nutritional status. DNA methylation at MEs was elevated in individuals conceived during the nutritionally challenged rainy season, providing the first evidence of a permanent, systemic effect of periconceptional environment on human epigenotype. At MEs, epigenetic regulation in internal organs and tissues varies among individuals and can be deduced from peripheral blood DNA. MEs should therefore facilitate an improved understanding of the role of interindividual epigenetic variation in human disease.