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Stochastic epigenetic variation as a driving force of development, evolutionary adaptation, and disease

Edited by Peter T. Ellison, Harvard University, Cambridge, MA, and approved November 17, 2009 (received for review September 2, 2009)
December 22, 2010
107 (suppl_1) 1757-1764

Abstract

Neo-Darwinian evolutionary theory is based on exquisite selection of phenotypes caused by small genetic variations, which is the basis of quantitative trait contribution to phenotype and disease. Epigenetics is the study of nonsequence-based changes, such as DNA methylation, heritable during cell division. Previous attempts to incorporate epigenetics into evolutionary thinking have focused on Lamarckian inheritance, that is, environmentally directed epigenetic changes. Here, we propose a new non-Lamarckian theory for a role of epigenetics in evolution. We suggest that genetic variants that do not change the mean phenotype could change the variability of phenotype; and this could be mediated epigenetically. This inherited stochastic variation model would provide a mechanism to explain an epigenetic role of developmental biology in selectable phenotypic variation, as well as the largely unexplained heritable genetic variation underlying common complex disease. We provide two experimental results as proof of principle. The first result is direct evidence for stochastic epigenetic variation, identifying highly variably DNA-methylated regions in mouse and human liver and mouse brain, associated with development and morphogenesis. The second is a heritable genetic mechanism for variable methylation, namely the loss or gain of CpG dinucleotides over evolutionary time. Finally, we model genetically inherited stochastic variation in evolution, showing that it provides a powerful mechanism for evolutionary adaptation in changing environments that can be mediated epigenetically. These data suggest that genetically inherited propensity to phenotypic variability, even with no change in the mean phenotype, substantially increases fitness while increasing the disease susceptibility of a population with a changing environment.

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Acknowledgments

We thank Elisabet Pujadas for providing helpful discussions and comments on the manuscript, Simon Tavaré for pointing out evolution papers containing simulations, and Sarah Wheelan for help with BLAST. This work was supported by National Institutes of Health Grants P50 HG003233 and R01 GM083084.

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Information & Authors

Information

Published in

Go to Proceedings of the National Academy of Sciences
Go to Proceedings of the National Academy of Sciences
Proceedings of the National Academy of Sciences
Vol. 107 | No. suppl_1
January 26, 2010
PubMed: 20080672

Classifications

    Submission history

    Published in issue: January 26, 2010
    Published online: December 22, 2010

    Keywords

    1. DNA methylation
    2. epigenetics
    3. evolution
    4. stochastic variation

    Acknowledgments

    We thank Elisabet Pujadas for providing helpful discussions and comments on the manuscript, Simon Tavaré for pointing out evolution papers containing simulations, and Sarah Wheelan for help with BLAST. This work was supported by National Institutes of Health Grants P50 HG003233 and R01 GM083084.

    Notes

    This paper results from the Arthur M. Sackler Colloquium of the National Academy of Sciences, “Evolution in Health and Medicine,” held April 2–3, 2009, at the National Academy of Sciences in Washington, DC. The complete program and audio files of most presentations are available on the NAS web site at www.nasonline.org/Sackler_Evolution_Health_Medicine.
    This article is a PNAS Direct Submission.

    Authors

    Affiliations

    Andrew P. Feinberg1 [email protected]
    Center for Epigenetics, Johns Hopkins University, Baltimore, MD 21205
    Rafael A. Irizarry
    Center for Epigenetics, Johns Hopkins University, Baltimore, MD 21205

    Notes

    1
    To whom correspondence should be addressed. E-mail: [email protected].
    Author contributions: A.P.F. designed research; A.P.F. and R.A.I. performed research; R.A.I. contributed new reagents/analytic tools; A.P.F. and R.A.I. analyzed data; and A.P.F. and R.A.I. wrote the paper.

    Competing Interests

    The authors declare no conflict of interest.

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      Stochastic epigenetic variation as a driving force of development, evolutionary adaptation, and disease
      Proceedings of the National Academy of Sciences
      • Vol. 107
      • No. suppl_1
      • pp. 1691-1807

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