Season of Conception in Rural Gambia Affects DNA Methylation at Putative Human Metastable Epialleles

TLDR

In mammals, most epigenetic states are genetically programmed, but at metastable epialleles (MEs) the epigenotype is set stochastically in the early embryo, producing systemic interindividual variation; MEs have not yet been identified in humans, although maternal nutrition influences them in mice. The authors aimed to identify putative MEs in the human genome and to test whether periconceptional nutrition in rural Gambia leaves a permanent epigenetic imprint. They employed a 2‑tissue parallel epigenomic screen to discover MEs and then examined methylation patterns in autopsy samples and in a cohort of Gambian individuals conceived during distinct seasonal nutritional periods. They found that human MEs exist, show methylation correlated across tissues, display stochastic variation in monozygotic twins, and are hyper‑methylated in individuals conceived during the nutritionally challenged rainy season, indicating a lasting, systemic effect of periconceptional environment that can be inferred from peripheral blood and may inform disease research.

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.