The Epigenetics Revolution

Of course, the standard answer has always been that discordancy between the twins is due to differences in their environments. Sometimes this is clearly true. If we were monitoring longevity, for example, one twin getting knocked over and killed by a number 47 bus would certainly represent an environmental difference. But this is an extreme scenario. Many twins share a fairly similar environment, especially in early development. Even so, it is certainly possible that there are multiple subtle environmental differences that may be hard to monitor appropriately.

But if we invoke the environment as the other important factor in development of disease, this raises another problem. It still leaves the question of how the environment does this. Somehow the environmental stimuli – be these compounds in our food, chemicals in cigarette smoke, UV rays in sunlight, pollutants from car exhausts or any of the thousands of molecules and radiation sources that we’re exposed to every day – must impact on our genes and cause a change in expression.

The majority of non-infectious diseases that afflict most people take a long time to develop, and then remain as a problem for many years if there is no cure available. The stimuli from the environment could theoretically be acting on the genes all the time in the cells that are acting abnormally, leading to disease. But this seems unlikely, especially because most of the chronic diseases probably involve the interaction of multiple stimuli with multiple genes. It’s hard to imagine that all these stimuli would be present for decades at a time. The alternative is that there is a mechanism that keeps the disease-associated cells in an abnormal state, i.e. expressing genes inappropriately.

In the absence of any substantial evidence for a role for somatic mutation, epigenetics seems like a strong candidate for this mechanism. This would allow the genes in one twin to stay mis-regulated, ultimately leading to a disease. We’re only at the beginning of the investigation but some evidence has started accumulating that suggests this may indeed be the case.

One of the most straightforward experiments conceptually, is to analyse if chromatin modification patterns (the epigenome) change as MZ twins get older. In the simplest case, we wouldn’t even need to investigate this in the context of disease. We could start by testing a much simpler hypothesis – that genetically identical individuals become epigenetically non-identical as they age. If this hypothesis is correct, this would support the idea that MZ twins can vary from each other at the epigenetic level. This in turn would strengthen our confidence in moving forwards to examining the role of epigenetic changes in disease.

In 2005, a large collaborative group headed by Professor Manel Esteller, then at the Spanish National Cancer Centre in Madrid, published a paper in which they examined this issue[31]. They made some interesting discoveries. If they examined chromatin from infant MZ twin pairs, they couldn’t see much difference in the levels of DNA methylation or of histone acetylation between the two twins. When they looked at pairs of MZ twins who were much older, such as in their fifties, there was a lot of variation within the pair for the amount of DNA methylation or histone acetylation. This seemed to be particularly true of twins that had lived apart for a long time.

The results from this study were consistent with a model where genetically identical twins start out epigenetically very similar, and then diverge as they get older. The older MZ twins who had led separate and different lives for the longest would be expected to be the ones who had encountered the greatest differences in their environments. The finding that these were precisely the twin pairs who were most different epigenetically was consistent with the idea that the epigenome (the overall pattern of epigenetic modifications on the genome) reflects environmental differences.

Children who eat breakfast are statistically more likely to do well at school than children who skip breakfast. This doesn’t necessarily mean that learning can be improved by a bowl of cornflakes. It may simply be that children who eat breakfast are more likely to be children whose parents make an effort to get them to school every day, on time, and help them with their studies. Similarly, Professor Esteller’s data are correlative. They show there is a relationship between the ages of twins and how different they are epigenetically, but they don’t prove that age has caused the change in the epigenome. But at least the hypothesis can remain in play.