With their identical genetic make-up, monozygotic twins are firm favourites for sorting out genetic effects from those of the environment. But in a recent study it was the differences between identical twins that made them such fascinating research subjects: widespread epigenetic differences between twins that accumulate over the years indicate an important way that age and the environment might affect human health.
Manel Esteller and colleagues measured the total levels of two key epigenetic modifications — DNA methylation and histone acetylation — across the genomes of 40 pairs of monozygotic twins. For 65% of the pairs the twins had almost identical epigenetic profiles, but for the remaining 35% there were significant differences. Interestingly, there was a clear relationship between the age of the twins and the amount of difference between them. The amount of epigenetic difference was also correlated with spending large amounts of time apart and having different medical histories. So changes accumulated over time or influenced by environmental factors seem to have important effects on the epigenome.
To determine the biological significance of these epigenetic differences, the authors used a methylation fingerprinting technique in which distinct DNA bands correspond to individual methylated regions. Sequencing the bands that differed between identical twins revealed that although 52% of them corresponded to repetitive regions, the remainder reflected changes at predicted or known genes.
Importantly, the regions that were differentially methylated between twins also included CpG islands located in promoter regions, indicating potential effects on gene expression. This was confirmed by microarray analysis: whereas the expression profiles for pairs of 3-year-old twins were almost identical, there were large differences between the profiles of 50-year-old twins.
Alterations in gene expression that arise from global epigenetic changes over time are likely to have an important influence on susceptibility to many types of disease. The next challenge will be to work out how these changes arise: do they result from the cumulative effects of defects in epigenetic maintenance or transmission, or do environmental factors such as diet and exposure to pollutants have a role?
ORIGINAL RESEARCH PAPER
Fraga, M. F. et al. Epigenetic differences arise during the lifetime of monozygotic twins. Proc. Natl Acad. Sci. 102, 10604–10609 (2005)
Fazzari, M. J. & Greally, J. M. Epigenomics: beyond CpG islands. Nature Rev. Genet. 5, 446–455 (2004)
Robertson, K. D. DNA methylation and human disease. Nature Rev. Genet. 6, 597–610 (2005)
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Flintoft, L. Identical twins: epigenetics makes the difference. Nat Rev Genet 6, 667 (2005). https://doi.org/10.1038/nrg1693