Abstract
BackgroundAlthough the genomes of monozygotic twins are practically identical, their methylomes may evolve divergently throughout their lifetime as a consequence of factors such as the environment or aging. Particularly for young and healthy monozygotic twins, DNA methylation divergence, if any, may be restricted to stochastic processes occurring post-twinning during embryonic development and early life. However, to what extent such stochastic mechanisms can systematically provide a stable source of inter-individual epigenetic variation remains uncertain until now.ResultsWe enriched for inter-individual stochastic variation by using an equivalence testing-based statistical approach on whole blood methylation microarray data from healthy adolescent monozygotic twins. As a result, we identified 333 CpGs displaying similarly large methylation variation between monozygotic co-twins and unrelated individuals. Although their methylation variation surpasses measurement error and is stable in a short timescale, susceptibility to aging is apparent in the long term. Additionally, 46% of these CpGs were replicated in adipose tissue. The identified sites are significantly enriched at the clustered protocadherin loci, known for stochastic methylation in developing neurons. We also confirmed an enrichment in monozygotic twin DNA methylation discordance at these loci in whole genome bisulfite sequencing data from blood and adipose tissue.ConclusionsWe have isolated a component of stochastic methylation variation, distinct from genetic influence, measurement error, and epigenetic drift. Biomarkers enriched in this component may serve in the future as the basis for universal epigenetic fingerprinting, relevant for instance in the discrimination of monozygotic twin individuals in forensic applications, currently impossible with standard DNA profiling.
Highlights
The genomes of monozygotic twins are practically identical, their methylomes may evolve divergently throughout their lifetime as a consequence of factors such as the environment or aging
We considered data derived from two methods: the Illumina Infinium HumanMethylation450K Beadchip array (450K), covering > 450,000 cytosineguanine dinucleotide (CpG) sites and the whole genome bisulfite sequencing (WGBS), currently considered as the gold standard in methylomics
Discovery of equivalently variableCpGs In search for CpGs displaying similar variation between MZ co-twins and unrelated individuals, an epigenome-wide discovery phase was implemented in 450K CpG methylation data derived from whole blood of 426 MZ twin pairs sampled at age 18 [5]
Summary
The genomes of monozygotic twins are practically identical, their methylomes may evolve divergently throughout their lifetime as a consequence of factors such as the environment or aging. The main drivers of inter-individual DNA methylation variation identified so far are genetics, sex, cell type/tissue, environment, and aging [5,6,7] The latter includes both the epigenetic clock, i.e., the direct association between CpG methylation and age across individuals, and the epigenetic drift, defined as individual-specific accumulation of stochastic and environmental changes over time [8, 9]. It was widely popularized that healthy monozygotic (MZ) twins sharing sex, age, and practically identical genomes display indistinguishable methylomes at a young age, while at an older age, differential exposures to environmental factors promote methylation divergence over time (epigenetic drift) [10, 11]. Metastable epiallele variation in MZ cotwins is limited due to the phenomenon of twin super-similarity; namely, a stochastic setting of methylation states prior to the twinning process results in identical methylation profiles for both twins [17]
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