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The molecular mechanisms responsible for the developmental origins of later disease are currently unknown. We previously demonstrated that women's periconceptional nutrition predicts their offspring's DNA methylation at metastable epialleles (MEs). We present a genome-wide screen yielding 687 MEs and track their trajectories across nine developmental stages in human in vitro fertilization embryos. MEs exhibit highly unusual methylation dynamics across the implantation-gastrulation transition, producing a large excess of intermediate methylation states, suggesting the potential for differential programming in response to external signals. Using a natural experiment in rural Gambia, we show that genomic regions sensitive to season of conception are highly enriched for MEs and show similar atypical methylation patterns. MEs are enriched for proximal enhancers and transcription start sites and are influenced by genotype. Together, these observations position MEs as distinctive epigenomic features programmed in the early embryo, sensitive to genetic and periconceptional environment, and with the potential to influence phenotype.

The article focuses on DNA methylation at a nutritionally sensitive region of the PAX8 gene is associated with thyroid volume and function in Gambian children. Topics include PAX8 is a key thyroid transcription factor implicated in thyroid gland differentiation and function, PAX8 gene methylation is reported to be sensitive to the periconceptional environment, and Free T4 was associated with a decrease in DXA-derived body fat and bone mineral density.