Epigenetic differences arise during the lifetime of monozygotic twins

Mario Fraga

Esteban Ballestar

Maria Paz

Santiago Ropero

Miguel Urioste+12 authors

^Epigenetics,^{Cytogenetics, and}^{Genetic Laboratories, Spanish National Cancer Centre (CNIO), Melchor Fernandez Almagro 3, 28029 Madrid, Spain;}^{Department of Behavioral Science, University of Valencia, 46010 Valencia, Spain;}^{Molecular Genetics Laboratory, Genetics Department, Son Dureta Hospital, 07014 Palma de Mallorca, Spain;}^{Department of Clinical Sciences, University Hospital Malmö, Lund University, S-205 02 Malmö, Sweden;}^{Steno Diabetes Center, 2820 Gentofte, Denmark;}^{Twin Research and Genetic Epidemiology Unit, St. Thomas' Hospital, London SE1 7EH, United Kingdom; and}^{Human Cancer Genetics Program, Department of Molecular Virology, Immunology, and Medical Genetics, Ohio State University, Columbus, OH 43210}

^{To whom correspondence should be addressed. E-mail:}se.oinc@relletsem.

Edited by Stanley M. Gartler, University of Washington, Seattle, WA

Received 2005 Jan 17; Accepted 2005 May 23.

Freely available online through the PNAS open access option.

Abstract

Monozygous twins share a common genotype. However, most monozygotic twin pairs are not identical; several types of phenotypic discordance may be observed, such as differences in susceptibilities to disease and a wide range of anthropomorphic features. There are several possible explanations for these observations, but one is the existence of epigenetic differences. To address this issue, we examined the global and locus-specific differences in DNA methylation and histone acetylation of a large cohort of monozygotic twins. We found that, although twins are epigenetically indistinguishable during the early years of life, older monozygous twins exhibited remarkable differences in their overall content and genomic distribution of 5-methylcytosine DNA and histone acetylation, affecting their gene-expression portrait. These findings indicate how an appreciation of epigenetics is missing from our understanding of how different phenotypes can be originated from the same genotype.

Keywords: DNA methylation, epigenetics, histones

Abstract

Human monozygotic (MZ) twins account for 1 in 250 live births (1). The origin of MZ twins is attributed to two or more daughter cells of a single zygote undergoing independent mitotic divisions, leading to independent development and births. They are considered genetically identical, but significant phenotypic discordance between them may exist. This quality is particularly noticeable for psychiatric diseases, such as schizophrenia and bipolar disorder (2). MZ twins have been used to demonstrate the role of environmental factors in determining complex diseases and phenotypes, but the true nature of the phenotypic discordance nevertheless remains extremely poorly understood. In this context, differences in the placenta, amniotic sac, and vascularization of the separate cell masses or even mosaicism in genetic and cytogenetic markers in MZ may exist (3), although the published studies are very few in number. Thus, the real causes for MZ twin discordance for common diseases and traits remain to be established. Epigenetic differences may be an important part of the solution to this puzzle. Indeed, epigenetic profiles may represent the link between an environmental factor and phenotypic differences in MZ twins. Cloned animals provide another example of how epigenetics may explain phenotypic differences in beings that have identical genetic sequences. In this case, inefficient epigenetic reprogramming of the transplanted nucleus is associated with aberrations in imprinting, aberrant growth, and lethality beyond a threshold of faulty epigenetic control (4). MZ twins are another phenomenon in which epigenetics can “make the difference.” To address this possibility, we have profiled the epigenetic patterns related to global and locus-specific DNA methylation and histone H3 and H4 acetylation in the largest series of MZ twins for which molecular studies have been reported.

Chr. loc., chromosome location; –, unknown.

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Acknowledgments

We thank all our volunteer twins and Sara Casado, Lidia Lopez-Serra, Miguel Alaminos, and Alicia Barroso from the Spanish National Cancer Centre. M.F.F. is funded by the Foundation of the Spanish Association Against Cancer (AECC).

Acknowledgments

Notes

This paper was submitted directly (Track II) to the PNAS office.

Abbreviations: AIMS, amplification of intermethylated sites; ESD, Euclidean squared distance; 5mC, 5-methylcytosine; MZ, monozygotic; RLGS, restriction landmark genomic scanning.

See Commentary on page 10413.

Notes

This paper was submitted directly (Track II) to the PNAS office.

Abbreviations: AIMS, amplification of intermethylated sites; ESD, Euclidean squared distance; 5mC, 5-methylcytosine; MZ, monozygotic; RLGS, restriction landmark genomic scanning.

See Commentary on page 10413.

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