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Cell Rep. 2018 Dec 4;25(10):2660-2667.e4. doi: 10.1016/j.celrep.2018.11.023.

Selective Survival of Embryos Can Explain DNA Methylation Signatures of Adverse Prenatal Environments.

Author information

1
Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center, 2300RC Leiden, the Netherlands; Human Nutrition and Health, Wageningen University & Research, 6708WE Wageningen, the Netherlands.
2
Institute for Cell and Molecular Biosciences, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne NE4 5PL, UK; Laboratory of Genetics, Wageningen University & Research, PO Box 16, 6700 AA Wageningen, the Netherlands.
3
Laboratory of Genetics, Wageningen University & Research, PO Box 16, 6700 AA Wageningen, the Netherlands.
4
Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center, 2300RC Leiden, the Netherlands; Department of Epidemiology, Mailman School of Public Health, Columbia University Medical Center, New York, NY 10032, USA.
5
Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center, 2300RC Leiden, the Netherlands. Electronic address: bas.heijmans@lumc.nl.
6
Edward Grey Institute, Department of Zoology, University of Oxford, South Parks Road, Oxford OX1 3PS, UK; Department of Biology, University of Lund, Sölvegatan 37, 22362 Lund, Sweden.

Abstract

An adverse intrauterine environment is associated with long-term physiological changes in offspring. These are believed to be mediated by epigenomic marks, including DNA methylation (DNAm). Changes in DNAm are often interpreted as damage or plastic responses of the embryo. Here, we propose that stochastic DNAm variation, generated during remodeling of the epigenome after fertilization, contributes to DNAm signatures of prenatal adversity through differential survival of embryos. Using a mathematical model of re-methylation in the early embryo, we demonstrate that selection, but not plasticity, will generate a characteristic reduction in DNAm variance at loci that contribute to survival. Such a reduction in DNAm variance was apparent in a human cohort prenatally exposed to the Dutch famine, illustrating that it is possible to detect a signature of selection on epigenomic variation. Selection should be considered as a possible mechanism linking prenatal adversity to subsequent health and may have implications when evaluating interventions.

KEYWORDS:

DNA methylation; developmental origins; plasticity; selection

PMID:
30517855
DOI:
10.1016/j.celrep.2018.11.023
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