To mark the passing of the sun into Gemini, this month Genome Biology has published a special issue on twin studies. Not really: we just had a lot of twin studies and they all fortuitously ended up being published in May. But they’re good studies, so we thought it was worth highlighting them here.
Human genomics is mostly correlative: a genetic variant is seen to be associated with a given phenotype. In some cases, the association might be strong enough to infer a cause, but as everyone knows, correlation is no proof of causation. Unfortunately, the sort of confirmatory functional work that might be possible in laboratory animals is usually frowned upon by pesky ethics committees if you propose it in humans. Fortunately, monozygotic twins can be very useful from this point of view, as they are a sort of biological replicate for your experiment. They are particularly useful for epigenetic studies, because with essentially identical genomes, any differences in epigenetic factors must be environmentally determined (or stochastic variation).
This is perhaps best exemplified by the study by Jörn Walter and colleagues. These researchers took 17 pairs of adult identical twins in which the two twins in each pair had been born with different weights. Since the twins had identical genomes, the weight differences must be environmentally determined. Walter’s team wanted to know if this would have had any effect on DNA methylation in the twins. As it happens, it seems that it did not. The co-twins showed very similar genome-wide DNA methylation profiles, with most observed differences being attributed to the cellular composition of the samples profiled. This would seem to imply that the major component contributing to methylation is genetic, and at least in the case of discordant birth weights, environmental factors have little impact.
In contrast, Jeffrey Craig and colleagues found that there must be at least some non-genetic factor in DNA methylation. The focus of their study was how methylation changes over time. They took ten pairs of identical twins and five pairs of fraternal twins and measured DNA methylation status at birth and then 18 months later. They found that, in general, methylation increases over time. They also found that pairs of twins tended to show differing changes in methylation. Thus, changes in methylation over time must have a large environmental or stochastic component, rather than being genetically determined.
Vardhman Rakyan and colleagues also found loci with differing methylation status between co-twins in their study of 33 pairs of monozygotic twins. Interestingly, these differences were found to be stable over time, at least in the small subset of subjects where this was tested. The genes where these differences were found tended to be those with little or no expression in the cell types studied.
The somewhat contrasting findings of these three studies – that twins may or may not have similar methylation profiles, and that any differences may or may not be stable over time – could be explained by a number of factors. Perhaps the choice of cell type studied makes a difference, or maybe even the definitions of ‘similar’ or ‘different’. Also, when a field is in its infancy it is not uncommon for apparently conflicting studies to be published until the field settles down and the conflicts are resolved. Whatever the final answer turns out to be on whether methylation status is largely genetically or environmentally determined, it is clear that twin studies are going to have a large part to play in sorting out this exciting field.
Andrew Cosgrove
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