The Epigenetics Revolution

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 three-fold 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}

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.