Trends in Genetics
Research FocusEpigenetics and twins: three variations on the theme
Introduction
Twin-based designs provide an estimate of the relative contribution of genetic and non-genetic factors to a specific phenotype. The basic principle is simple: monozygotic (MZ) twins have identical genomes and dizygotic (DZ) twins share only half of their segregating DNA, and therefore the contribution of genetic factors to a specific trait should be twice the difference of concordance rates between MZ twins and DZ twins. By contrast, phenotypic differences in genetically identical twins are usually treated as a proof of an environmental contribution. Although detecting formal evidence for environmental contributions is relatively trivial, uncovering the specific environmental factors has been hampered by methodological complexities, primarily unclear cause–effect relationships between a specific environmental factor and a phenotype [1]. Although epidemiological studies, as a rule, depend on the assumptions and biases of researchers, large-scale epigenetic and gene expression studies of twins might become a productive means of understanding the impact of the environment on the organism, cell and genome.
There is now increasing evidence that DNA and chromatin modifications react to various types of environmental effects. In plants, flowering by prolonged cold – vernalization – involves changes in histone modification in the discrete domains of genes that encode repressors of flowering [2]. In Drosophila, environmental stress or drugs, via chaperone Hsp90, increase the activity of a histone H3 lysine 4 methyltransferase, which activates the chromatin of target genes and exposes previously hidden morphological phenotypes [3]. A series of experiments has demonstrated an epigenetic impact of carcinogenic agents on modifications of DNA and histones [4]. Interestingly, increased pup licking, grooming and arched-back nursing by rat mothers altered the DNA methylation and histone modifications in the promoter of a glucocorticoid receptor gene, expressed in the hippocampus of their offspring [5]. These studies suggest that epigenetic modifications can be a molecular substrate for the impact of the endogenous and exogenous environment. The attempt to dissect complex multidirectional environmental effects can be substituted by a novel indirect approach that would first aim to uncover the molecular epigenetic impact of such effects, and then identify the specific causal factors behind such epigenetic changes. In this article, I discuss three relevant aspects: epigenetic differences in twins; epigenetic similarities in twins; and quantitative epigenetics.
Section snippets
Epigenetic differences in twins
A comparison of identical twins is an ideal design for testing environmental epigenetics, because DNA sequence differences that would be abundant in a singleton-based study is not a confounding factor. There are already several studies searching for epigenetic differences between identical twins. A disease-specific DNA methylation difference, an imprinting defect at KCNQ1OT1, was detected in MZ twins affected with Beckwith–Wiedemann syndrome but not in their healthy co-twins [6]. A traditional
Epigenetic similarities in twins
The other side of the ‘coin’ – epigenetic similarities in identical twins – has not been explored yet, although this is an equally interesting and important aspect of complex non-mendelian biology. Although traditionally all phenotypic similarities in MZ twins are explained by their DNA sequence identity, there is no reason to exclude epigenetic contributions. If epigenetic differences can result in different phenotypes, could epigenetic similarities be the molecular reason for some phenotypic
Epigenetics and twins in a wider context: quantitative epigenetics
While discussing epigenetic mechanisms of induced heritable morphological alterations in Drosophila melanogaster, Rutherford and Henikoff introduced the term ‘quantitative epigenetics’ to acknowledge the role of epigenetic inheritance in complex traits, which are often called quantitative traits in model organisms [25]. Quantitative genetics, the ‘older sib’ of quantitative epigenetics, has been a dynamic field and in the past several decades thousands of quantitative trait loci (QTLs) have
Concluding remarks
Studies of epigenetic differences and similarities of twins bring a new perspective to the various phenomenological, clinical and molecular aspects of non-mendelian biology, new laboratory technologies and also a new hope that the mystery of complex traits can be ‘unlocked’ in the near future. Interestingly, twins have been used in genetic studies for more than half a century and some epigenetic factors (e.g. methylated cytosines) were identified long before the structure of DNA was discovered.
Acknowledgements
I thank Irving Gottesman (University of Minnesota) and Jonathan Mill (Centre for Addiction and Mental Health, Toronto) for their comments and suggestions. This research has been supported by the grants from NIH (R01 MH074127-01), Canadian Institutes for Health Research, Ontario Mental Health Foundation, NARSAD and the Stanley Foundation.
References (28)
Metastable epialleles in mammals
Trends Genet.
(2002)How the mouse got its spots
Trends Genet.
(2004)- et al.
Epigenetic germline inheritance
Curr. Opin. Genet. Dev.
(2004) - et al.
Transgenerational epigenetic inheritance
Curr. Biol.
(2003) Human morbid genetics revisited: relevance of epigenetics
Trends Genet.
(2001)Epidemiology faces its limits
Science
(1995)Vernalization, competence, and the epigenetic memory of winter
Plant Cell
(2004)Hsp90 and environmental impacts on epigenetic states: a model for the trans-generational effects of diethylstibesterol on uterine development and cancer
Hum. Mol. Genet.
(2005)- et al.
Epigenetics and the environment
Ann. N. Y. Acad. Sci.
(2003) Epigenetic programming by maternal behavior
Nat. Neurosci.
(2004)
Discordant KCNQ1OT1 imprinting in sets of monozygotic twins discordant for Beckwith–Wiedemann syndrome
Hum. Mol. Genet.
Monozygotic twins exhibit numerous epigenetic differences: clues to twin discordance?
Schizophr. Bull.
Epigenetic differences arise during the lifetime of monozygotic twins
Proc. Natl. Acad. Sci. U. S. A.
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