Abstract
Monozygotic (MZ) twins share nearly all of their genetic variants and many similar environments before and after birth. However, they can also show phenotypic discordance for a wide range of traits. Differences at the epigenetic level may account for such discordances. It is well established that epigenetic states can contribute to phenotypic variation, including disease. Epigenetic states are dynamic and potentially reversible marks involved in gene regulation, which can be influenced by genetics, environment, and stochastic events. Here, we review advances in epigenetic studies of discordant MZ twins, focusing on disease. The study of epigenetics and disease using discordant MZ twins offers the opportunity to control for many potential confounders encountered in general population studies, such as differences in genetic background, early-life environmental exposure, age, gender, and cohort effects. Recently, analysis of disease-discordant MZ twins has been successfully used to study epigenetic mechanisms in aging, cancer, autoimmune disease, psychiatric, neurological, and multiple other traits. Epigenetic aberrations have been found in a range of phenotypes, and challenges have been identified, including sampling time, tissue specificity, validation, and replication. The results have relevance for personalized medicine approaches, including the identification of prognostic, diagnostic, and therapeutic targets. The findings also help to identify epigenetic markers of environmental risk and molecular mechanisms involved in disease and disease progression, which have implications both for understanding disease and for future medical research.
Highlights
Epigenetics emerged during the first half of the 20th century as the study of biological mechanisms involved in embryonic development and cell differentiation [1]
It has been defined as the study of nuclear inheritance through cell division that is not based on differences in DNA sequence [2] and includes any mechanism that alters gene expression without altering DNA sequence
DNA methylation of cytosines at CpG dinucleotides was proposed as a mechanism of mammalian gene regulation in 1975 [3,4], and as it is the best studied epigenetic mechanism in human populations we will concentrate on it in this review
Summary
Epigenetics emerged during the first half of the 20th century as the study of biological mechanisms involved in embryonic development and cell differentiation [1]. Epigenetic findings from disease-discordant MZ twin studies so far have identified DNA methylation changes in multiple genes across a wide range of phenotypes. In some cases, such as DOK7 in breast cancer, the identified changes are likely biomarkers of disease but may be involved in disease susceptibility as they pre-date the cancer diagnosis. Key challenges in epigenetic studies of disease-discordant MZ twins predominantly relate to sample size and power, choice and availability of appropriate tissue for the trait of interest, maximizing DNA methylation array coverage and sensitivity, and integrating epigenetic profiles with genetic, transcription, and environmental datasets (Box 1). Competing interests The authors declare that they have no competing interests
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