title: Season of conception in rural gambia affects DNA methylation at putative human metastable epialleles.
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.
authors.affiliation: Department of Pediatrics, Baylor College of Medicine, USDA/ARS Children's Nutrition Research Center, Houston, Texas, United States of America. waterland@bcm.edu
authors.forename: Robert A
authors.initials: RA
authors.lastname: Waterland
authors.forename: Richard
authors.initials: R
authors.lastname: Kellermayer
authors.forename: Eleonora
authors.initials: E
authors.lastname: Laritsky
authors.forename: Pura
authors.initials: P
authors.lastname: Rayco-Solon
authors.forename: R Alan
authors.initials: RA
authors.lastname: Harris
authors.forename: Michael
authors.initials: M
authors.lastname: Travisano
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Zhang
authors.forename: Maria S
authors.initials: MS
authors.lastname: Torskaya
authors.forename: Jiexin
authors.initials: J
authors.lastname: Zhang
authors.forename: Lanlan
authors.initials: L
authors.lastname: Shen
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Manary
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Prentice
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D002648:Child; D002675:Child, Preschool; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D005306:Fertilization; D005714:Gambia; D056426:Genetic Loci; D005826:Genetics, Medical; D006801:Humans; D007223:Infant; D008297:Male; D051379:Mice; D008875:Middle Aged; D012424:Rural Population; D012621:Seasons; D014430:Twins, Monozygotic / Q000235:genetics; D055815:Young Adult