Why Identical Twins Aren't Identical: Epistasis and Its Evolutionary Implications - Evolution News & Views

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Why Identical Twins Aren't Identical: Epistasis and Its Evolutionary Implications

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How come two people can have the same genetic mutation yet only one of them gets the disease associated with it? The question, which has troubling implications for evolutionary theory, is really asking what drives or inhibits the expression of certain mutations. After all, it is not enough that a genetic mutation occurs; it must also be "turned on" for it to operate.

Recently scientists have studied the occurrence of schizophrenia in monozygotic (identical) twins in order to determine why one twin had schizophrenia and the other did not. If schizophrenia is a purely genetic disease, then both twins should have schizophrenia. As it turns out, 1) more than genetic and environmental factors affect schizophrenia and 2) identical twins are not genetically identical.

The simple model was that some people get certain diseases for two reasons: 1) genetic variances, and/or 2) environmental factors. However, studies with bacteria indicate that there may be other factors that influence the activation or inhibition of genetic mutations. Indeed, anyone who has ever interacted with identical twins realizes that beneath the surface-level resemblance they are quite different, even though they likely had similar environments growing up and similar (although not identical) genetics.

In a new study published in Nature, scientists tried to determine the additional factors that affect the incidence of mutation expression and quantify the associated changes in the individual. They hoped thereby to learn to predict which genes (or factors) are relevant for the expression of a mutation. They used Caenorhabditis elegans as their model organism because its genome is well studied and its environment easily controlled.

The authors showed that in some cases two genes are ancestral duplicates and may therefore be epistatic, meaning that the expression of one gene affects or depends on another gene. (See this article for a background on epistasis: "Epistasis: what is it, what does it mean, and statistical methods to detect it in humans" Hum. Mol. Genet. (2002) 11 (20): 2463-2468.) In other cases, mutations may be dependent on variations of certain buffers, such as chaperone proteins.

What are the evolutionary implications, of epistasis in particular? The mechanism of evolutionary change is random mutations coupled with natural selection. If a mutation is affected by other mutations, other genes, or other proteins, then this will affect the rate of adaptation. (See "Negative Epistasis between Beneficial Mutations in an Evolving Bacterial Population" Science 3 June 2011: Vol. 332 no. 6034 pp. 1193-1196; and "Diminishing Returns Epistasis Among Beneficial Mutations Decelerates Adaption" Science 3 June 2011: Vol. 332 no. 6034 pp. 1190-1192.)

If multiple factors must be in place for an advantageous mutation not only to be expressed but also to be selected for, then the rate of evolutionary change would be significantly slower. In many cases, several beneficial mutations end up slowing the rate of adaptation. This may be due to an organism's reaching an optimal level of fitness for its particular environment, or it may be due to the deleterious effects of accumulated mutations. In other words, while one mutation may be beneficial, several independently beneficial mutations when acting together may not be beneficial.

The Nature report focuses on the role of chaperone proteins, particularly in development, by measuring the expression of two known mutations as a result of the activity or inactivity of a particular chaperone protein (DAF-21). The authors found that "[h]igher chaperone expression during early embryonic development therefore predicts a reduced effect of the inherited mutation."

They contend that these changes are random variances that occur in development. However, how these chaperones play a role in inhibiting or advancing evolutionary adaptation is still in doubt. (See "Molecular Chaperones and Selection against Mutations" Biology Direct 2008 3:5 for an article on how chaperones affect evolutionary adaptation.)

Implications for design theory

The genome is highly specific and complex. With every study that reveals another layer of complexity, it becomes more and more difficult to attribute evolutionary progress to an accumulation of random factors. This study shows that in a given organism, not only does a random mutation have to take place, it needs to be a beneficial mutation, and it needs to have the right factors in place for it to be expressed. In the case of C. elegans, the mutation tbx-9 is affected both by tbx-8 and by chaperon proteins. This implies that multi-mutation features might be prevalent.

Implications for medicine

One of the goals of the Human Genome Project was to understand genetic factors that cause disease, and to eventually design tailor-made drugs to target particular diseases. However, due to the complexity of interactions in the genome, this has proved more difficult than expected. The authors of the Nature article sought to uncover some of the factors that come into play. From a report in Science Daily:

The work suggests that, even if we completely understand all of the genes important for a particular human disease, we may never be able to predict what will happen to each person from their genome sequence alone. Rather, to develop personalized and predictive medicine it will also be necessary to consider the varying extent to which genes are turned on or off in each person.
In the context of designing tailor-made drugs, it is unclear if this is helpful or whether perhaps it makes things more difficult. On one hand, in combating a disease, it may provide more than one point of attack. On the other hand, it becomes significantly harder to determine the factors that cause disease and predict whether someone will actually acquire the disease. With many diseases, genetic markers only indicate possibility, sometimes probability, but (usually) not certainty.

Photo credit: Spc. Roland Hale