Epigenetic differences arise during the lifetime of monozygotic twins

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.DNA methylation ͉ epigenetics ͉ histones H uman 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. Materials and MethodsSubjects. Eighty volunteer Caucasian twins from Spain were recruited in the study, including 30 male and 50 female subje...

DNA methylation and healthy human aging

“…Microarray studies confirmed a decrease in DNA methylation with age, while site‐specific analysis indicated an increase in variability of DNA methylation with age. The latter was first noted in monozygotic twins, and subsequently in unrelated individuals (Fraga et al ., 2005; Martin, 2005; Poulsen et al ., 2007; Kaminsky et al ., 2009; Martino et al ., 2011). These studies also supported the idea that DNA methylation showed reduced stringency in maintenance over the lifespan, resulting in an increase in interindividual variability along with the overall decrease in DNA methylation.…”

“…Epigenetic drift is now understood to comprise age‐related changes in the epigenome that include those that are acquired environmentally as well as stochastically (Fraga et al ., 2005; Fraga & Esteller, 2007; Kaminsky et al ., 2009; Hannum et al ., 2013; Teschendorff et al ., 2013). Early indications of epigenetic drift were noted in cell culture studies, after the observation that clones of a single cell line became epigenetically divergent upon multiple passages (Humpherys et al ., 2001).…”

Implementing a method for studying longitudinal DNA methylation variability in association with age

“…However, studying age-varying methylation sites captures divergence of methylomes between individuals over time, usually described as epigenetic drift . Studies on epigenetic drift have been conducted using various methods, which include observing methylation differences between monozygotic twins [6,7], counting extreme methylation outliers as epigenetic mutations [8] and computing methylation variability using a test of heteroskedasticity [1,9].

10.1080/15592294.2018.1521222-F0001Figure 1.Simplified plots illustrating the concept of age-associated and age-varying methylation patterns.

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Advanced aging phenotype is revealed by epigenetic modifications in rat liver after in utero malnutrition

“…There is evidence that these factors may strengthen DNA methylation stability or influence its deviation between genetically identical individuals over time (Shah et al ., 2014). Studies of monozygotic twins demonstrate widening epigenetic divergence over time, which correlates to greater interindividual variability in phenotype (Fraga et al ., 2005). Fraga et al .…”

“…Fraga et al . (2005) showed growing DNA methylation differences with age, especially in twin pairs whose lifestyle, location, and/or health status were disparate (Fraga et al ., 2005), defining DNA methylation as a dynamic mark able to record a variety of exposures at the cellular level. Recent studies have also demonstrated that methylation across tissues and cell types can be correlated with chronological age, indicating that DNA methylation certainly works as a function of age or can be accelerated by different conditions, most notably in the setting of cancer (Hannum et al ., 2013).…”