Read The Epigenetics Revolution Online
Authors: Nessa Carey
Tags: #Science/Life Sciences/Genetics and Genomics
The Epigenetics Revolution (12 page)
The scientific term for identical twins is monozygotic (MZ) twins. They were both derived from the same single-cell zygote formed from the fusion of one egg and one sperm. In the case of MZ twins the inner cell mass of the blastocyst split into two during the early cell divisions, like slicing a doughnut in half, and gave rise to two embryos. And these embryos are
genetically
identical.
genetically
identical.
This splitting of the inner cell mass to form two separate embryos is generally considered a random event. This is consistent with the frequency of MZ twins being pretty much the same throughout all human populations, and with the fact that identical twins don’t run in families. We tend to think of MZ twins as being very rare but this isn’t really the case. About one in every 250 full-term pregnancies results in the birth of a pair of MZ twins, and there are around ten million pairs of identical twins around the world today.
MZ twins are particularly fascinating because they help us to determine the degree to which genetics is the driving force for life events such as particular illnesses. They basically allow us to explore mathematically the link between the sequences of our genes (genotype) and what we are like (phenotype), be this in terms of height, health, freckles or anything else we would like to measure. This is done by calculating how often both twins in a pair present with the same disease. The technical term for this is the concordance rate.
Achondroplasia, a relatively common form of short-limbed dwarfism, is an example of a condition in which MZ twins are almost invariably affected in the same way. If one twin has achondroplasia, so does the other one. The disease is said to show 100 per cent concordance. This isn’t surprising as achondroplasia is caused by a specific genetic mutation. Assuming that the mutation was present in either the egg or the sperm that fused to form the zygote, all the daughter cells that form the inner cell mass and ultimately the two embryos will also carry the mutation.
However, relatively few conditions show 100 per cent concordance, as the majority of illnesses are not caused by one overwhelming mutation in a key gene. This creates the problem of how to determine if genetics plays a role, and if so, how great this role is. This is where twin studies have become so valuable. If we study large groups of MZ twins we can determine what percentage of them is concordant or discordant for a particular condition. If one twin has a disease, does the other twin also tend to develop it as well?
Figure 5.1
is a graph showing concordance rates for schizophrenia. This shows that the more closely related we are to someone with this disease, the more likely we are to develop it ourselves. The most important parts of the graph to look at are the two bars at the bottom, which deal with twins. From this we can compare the concordance rates for identical and non-identical (fraternal) twins. Non-identical twins share the same developmental environment (the uterus) but genetically are no more similar than any other pair of siblings, as they arose from two separate zygotes as a consequence of the fertilisation of two eggs. The comparison between the two types of twins is important because generally speaking, the twins in a pair (whether identical or non-identical) are likely to have shared pretty similar environments. If schizophrenia was caused mainly by environmental factors, we would expect the concordance rates for the disease to be fairly similar between identical and non-identical twins. Instead, what we see is that in non-identical twins, if one twin develops schizophrenia, the other twin has a 17 per cent chance of doing the same. But in MZ twins this risk jumps to nearly 50 per cent. The almost threefold higher risk for identical versus non-identical twins tells us that there is a major genetic component to schizophrenia.
is a graph showing concordance rates for schizophrenia. This shows that the more closely related we are to someone with this disease, the more likely we are to develop it ourselves. The most important parts of the graph to look at are the two bars at the bottom, which deal with twins. From this we can compare the concordance rates for identical and non-identical (fraternal) twins. Non-identical twins share the same developmental environment (the uterus) but genetically are no more similar than any other pair of siblings, as they arose from two separate zygotes as a consequence of the fertilisation of two eggs. The comparison between the two types of twins is important because generally speaking, the twins in a pair (whether identical or non-identical) are likely to have shared pretty similar environments. If schizophrenia was caused mainly by environmental factors, we would expect the concordance rates for the disease to be fairly similar between identical and non-identical twins. Instead, what we see is that in non-identical twins, if one twin develops schizophrenia, the other twin has a 17 per cent chance of doing the same. But in MZ twins this risk jumps to nearly 50 per cent. The almost threefold higher risk for identical versus non-identical twins tells us that there is a major genetic component to schizophrenia.
Figure 5.1
The concordance rates for schizophrenia. The more genetically related two individuals are, the more likely it is that if one individual has the disease, their relative will also develop the disorder. However, even in genetically identical monozygotic twins, the concordance rate for schizophrenia does not reach 100 per cent. Data taken from
The Surgeon General’s Report on Mental Health
http://www.surgeongeneral.gov/library/mentalhealth/chapter4/sec4_1.html#etiology
The concordance rates for schizophrenia. The more genetically related two individuals are, the more likely it is that if one individual has the disease, their relative will also develop the disorder. However, even in genetically identical monozygotic twins, the concordance rate for schizophrenia does not reach 100 per cent. Data taken from
The Surgeon General’s Report on Mental Health
http://www.surgeongeneral.gov/library/mentalhealth/chapter4/sec4_1.html#etiology
Similar studies have shown that there is also a substantial genetic component to a significant number of other human disorders, including multiple sclerosis, bipolar disorder, systemic lupus erythematosus and asthma. This has been really useful in understanding the importance of genetic susceptibility to complex diseases.
But in many ways, it’s the other side of the question that is more interesting. It’s not the MZ twins who both develop a specific disease who are most interesting. It’s the MZ twins who end up with very different outcomes – one a paranoid schizophrenic, one mentally very healthy, for example – who create the most intriguing scientific problem. Why do two genetically identical individuals, who in many cases have experienced very similar environments, have such variable phenotypes? Similarly, why is it quite rare for both MZ twins in a pair to develop type 1 diabetes? What is it, in addition to the genetic code, that governs these health outcomes?
How epigenetics drives a wedge between twins
One possible explanation would be that quite randomly the twin with schizophrenia had spontaneously developed mutations in genes in certain cells, for example in the brain. This could happen if the DNA replication machinery had malfunctioned at some point during brain development. These changes might increase his or her susceptibility to a disorder. This is theoretically possible, but scientists have failed to find much data to support this theory.
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
1
. 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.
1
. 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.
caused
the change in the epigenome. But at least the hypothesis can remain in play.
A team led by Dr Jeffrey Craig in 2010 at the Royal Children’s Hospital in Melbourne also examined DNA methylation in identical and fraternal twin pairs
2
. They investigated a few relatively small regions of the genome in greater detail than in Manel Esteller’s earlier paper. Using samples just from newborn twin pairs, they showed that there was a substantial amount of difference between the DNA methylation patterns of fraternal twins. This isn’t unexpected, since fraternal twins are genetically nonidentical and we expect different individuals to have different epigenomes. Interestingly, though, they also found that even the MZ twins differed in their DNA methylation patterns, suggesting identical twins begin to diverge epigenetically during development in the uterus. Combining the information from the two papers, and from additional studies, we can conclude that even genetically identical individuals are epigenetically distinct by the time of birth, and these epigenetic differences become more pronounced with age and exposure to different environments.
2
. They investigated a few relatively small regions of the genome in greater detail than in Manel Esteller’s earlier paper. Using samples just from newborn twin pairs, they showed that there was a substantial amount of difference between the DNA methylation patterns of fraternal twins. This isn’t unexpected, since fraternal twins are genetically nonidentical and we expect different individuals to have different epigenomes. Interestingly, though, they also found that even the MZ twins differed in their DNA methylation patterns, suggesting identical twins begin to diverge epigenetically during development in the uterus. Combining the information from the two papers, and from additional studies, we can conclude that even genetically identical individuals are epigenetically distinct by the time of birth, and these epigenetic differences become more pronounced with age and exposure to different environments.
Of mice and men (and women)
These data are consistent with a model where epigenetic changes could account for at least some of the reasons why MZ twins aren’t phenotypically identical, but there’s still a lot of supposition involved. That’s because for many purposes humans are a quite hopeless experimental system. If we want to be able to assess the role of epigenetics in the problem of why genetically identical individuals are phenotypically different from one another, we would like to be able to do the following:
1. Analyse hundreds of identical individuals, not just pairs of them;
2. Manipulate their environments, in completely controlled ways;
3. Transfer embryos or babies from one mother to another, to investigate the effects of early nurture;
4. Take all sorts of samples from the different tissues of the body, at lots of different time points;
5. Control who mates with whom;
6. Carry out studies on four or five generations of genetically identical individuals.
Needless to say, this isn’t feasible for humans.
This is why experimental animals have been so useful in epigenetics. They allow scientists to address really complex questions, whilst controlling the environment as much as possible. The data that are generated in these animal studies produce insights from which we can then try to infer things about humans.
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