Trends in Genetics
Volume 22, Issue 7, July 2006, Pages 347-350
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Research Focus
Epigenetics and twins: three variations on the theme

https://doi.org/10.1016/j.tig.2006.04.010Get rights and content

Twin studies have had a key role in the evaluation of heritability, a population-based estimate of the genetic contribution to phenotypic variation. These studies have led to the revelation that most normal and disease phenotypes are to some extent heritable. Recently, interest has shifted from phenomenological heritability to the identification of trait-specific genes. The era of twin studies, however, is not over: recent epigenetic and global gene expression studies suggest that the most interesting findings in twin-based research are still to come. The increasing realization of the influence of epigenetics in phenotypic outcomes means that the molecular mechanisms behind phenotypic differences in genetically identical organisms can be explored. Analyses of epigenetic twin differences and similarities might yet challenge the fundamental principles of complex biology, primarily the dogma that complex phenotypes result from DNA sequence variants interacting with the environment.

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.

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