Epigenetic supersimilarity of monozygotic twin pairs

Authors: VAN BAAK, TIMOTHY - Children'S Nutrition Research Center (CNRC); COARFA, CRISTIAN - Baylor College Of Medicine; DUGUE, PIERRE-ANTOINE - University Of Melbourne; FIORITO, GIOVANNI - University Of Toronto; LARITSKY, ELEONORA - Children'S Nutrition Research Center (CNRC); BAKER, MARIA - Children'S Nutrition Research Center (CNRC); KESSLER, NOAH - Children'S Nutrition Research Center (CNRC); DONG, JIANRONG - Baylor College Of Medicine; DURYEA, JACK - Children'S Nutrition Research Center (CNRC); SILVER, MATT - Children'S Nutrition Research Center (CNRC); SAFFARI, AYDEN - Children'S Nutrition Research Center (CNRC); PRENTICE, ANDREW - Children'S Nutrition Research Center (CNRC); MOORE, SOPHIE - Children'S Nutrition Research Center (CNRC); GHANTOUS, AKRAM - International Agency For Research On Cancer; ROUTLEDGE, MICHAEL - International Agency For Research On Cancer; GONG, YUN YUN - University Of Leeds; HERCEG, ZDENKO - King'S College; VINEIS, PAOLO - University Of Leeds; SEVERI, GIANLUCA - University Of Melbourne; HOPPER, JOHN - University Of Melbourne; SOUTHEY, MELISSA - Universite Paris Descartes; GILES, GRAHAM - Cancer Council Victoria; MILNE, ROGER - Cancer Council Victoria; WATERLAND, ROBERT - Children'S Nutrition Research Center (CNRC)

Submitted to: Genome Biology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/6/2017
Publication Date: 1/9/2018
Citation: Van Baak, T.E., Coarfa, C., Dugue, P., Fiorito, G., Laritsky, E., Baker, M.S., Kessler, N.J., Dong, J., Duryea, J.D., Silver, M.J., Saffari, A., Prentice, A.M., Moore, S.E., Ghantous, A., Routledge, M.N., Gong, Y., Herceg, Z., Vineis, P., Severi, G., Hopper, J.L., Southey, M.C., Giles, G.G., Milne, R.L., Waterland, R.A. 2018. Epigenetic supersimilarity of monozygotic twin pairs. Genome Biology. https://doi.org/10.1186/s13059-017-1374-0.

Interpretive Summary: The behavioral and physical similarities of monozygotic (‘identical’) twins are generally thought to be largely due to their genetic identity. In addition to genetics, however, many characteristics of organisms can be determined by epigenetic mechanisms, which are established during development then stably maintained throughout life. We analyzed a previously published genome-scale data set on DNA methylation (a key epigenetic mark) in a large group of monozygotic and dizygotic twin pairs. We identified a set of genomic regions at which the epigenetic similarity of monozygotic twins is greater than can be explained by their genetic identity. We call this phenomenon ‘epigenetic supersimilarity’ (ESS). We provide evidence that ESS reflects early embryonic establishment of DNA methylation, prior to the embryo cleavage that results in monozygotic twins. Also, we show that establishment of DNA methylation at these loci is influenced by maternal environment around the time of conception and predicts risk of various types of cancer in adulthood. ‘Heritability’ (i.e. the proportion of phenotypic variation explained by genetics) has, for decades, been estimated by studies of monozygotic and dizygotic twins. Hence, to the extent that ESS affects phenotype (as our data indicate), previous estimates of heritability of a wide range of traits have been exaggerated.

Technical Abstract: Monozygotic twins have long been studied to estimate heritability and explore epigenetic influences on phenotypic variation. The phenotypic and epigenetic similarities of monozygotic twins have been assumed to be largely due to their genetic identity. Here, by analyzing data from a genome-scale study of DNA methylation in monozygotic and dizygotic twins, we identified genomic regions at which the epigenetic similarity of monozygotic twins is substantially greater than can be explained by their genetic identity. This “epigenetic supersimilarity” apparently results from locus-specific establishment of epigenotype prior to embryo cleavage during twinning. Epigenetically supersimilar loci exhibit systemic interindividual epigenetic variation and plasticity to periconceptional environment and are enriched in sub-telomeric regions. In case-control studies nested in a prospective cohort, blood DNA methylation at these loci years before diagnosis is associated with risk of developing several types of cancer. These results establish a link between early embryonic epigenetic development and adult disease. More broadly, epigenetic supersimilarity is a previously unrecognized phenomenon that may contribute to the phenotypic similarity of monozygotic twins.