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Painting a Better Picture of Twin Discordance

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13 July 2005. Twin discordance—the manifestation of vastly different behaviors and susceptibilities to disease despite genetic identity—is a bit of a mystery. Some might attribute it to exposure to quite different environments after birth. But is this nurture argument sufficient to explain why one identical twin falls victim to something like Alzheimer disease, for example, while the other does not?

An international study led by Manel Esteller at the Spanish National Cancer Center in Madrid paints a slightly more detailed picture of twin discordance. Reporting in last week’s PNAS online, first author Mario Fraga and colleagues show that as twins age they accumulate vast numbers of epigenetic differences. In short, nurture may be altering nature.

Epigenetic differences, such as DNA methylation or histone acetylation, can have a profound impact on gene expression. To see if this might explain twin discordance, Fraga and colleagues, including researchers in Spain, Sweden, England, and the US, examined DNA and histone modification patterns in tissue samples taken from 80 identical (monozygotic) twins (30 female, 50 male). The authors found that in very young twins (3 years old), there were no statistical differences in overall cytosine methylation or in acetylation of histones H3 and H4. Samples from older twins told a different story, however. While the majority of twin pairs exhibited few differences, in 35 percent of twin pairs, all three parameters varied considerably. In one pair of 50-year-old twins, DNA methylation was 3.5 percent in one twin and 4.5 percent in the other, while histone H3 and H4 acetylations were about 60 vs. 48 percent and 24 vs. 18 percent, respectively.

The data suggest that in at least some cases, epigenetic characteristics that were similar close to birth have diverged as the twins aged. What’s more, this divergence may have an impact on health. Fraga and colleagues found that those twins who had discernibly different health and medical histories were those who had the greatest epigenetic differences. Twins who spent less of their lifetimes together also turned out to have greater epigenetic discordance than those who were closely knit.

For the most part, Fraga and colleagues focused on changes in lymphocytes. But they also examined epigenetic profiles of epithelial, fat, and skeletal muscle cells, finding similar patterns of divergence as for the blood cells. Functionally, the differences do seem important. For example, when the authors examined loci where methylation differences were observed, they found that about 34 percent of the loci matched expressed sequence tags, while 13 percent matched single copy genes. Zeroing in on a few specific sequences, Fraga and colleagues found that a pattern of hypomethylation in one twin and hypermethylation in the other was common.

So might these differences affect gene expression? To answer that, the authors used gene array analysis to compare mRNA levels between twins. They found that, as with methylation and acetylation patterns, portraits of gene expression showed the greatest differences in older twins and that transcript levels correlated with epigenetic changes. Twins with the most severe hypomethylation and hyperacetylation, for example, had the highest numbers of overexpressed genes, up to almost 4,000.

What seems clear from this study is that epigenetic changes can accumulate as people age. What is less clear is the cause of these changes. The authors suggest that they could be due to “epigenetic drift,” defects in the transmission of epigenetic changes during cell division. But they also suggest that external factors such as smoking habits, physical activity, or diet can also be influential, a suggestion backed up by the fact that twins with the most divergent natural health histories also had the greatest epigenetic differences. In the wider context of disease, “our comparison of MZ [monozygotic] twins suggests that external and/or internal factors can have an impact in the phenotype by altering the pattern of epigenetic modifications and thus modulating genetic information,” conclude the authors.—Tom Fagan.

Fraga MF, Ballestar E, Paz MF, Ropero S, Setien F, Ballestar ML, Heine-Suner D, Cigudosa JC, Ruioste M, Benitez J, Boix-Chornet M, Sanchez-Aguilera A, Ling C, Carlsson E, Poulsen P, Vaag A, Stephan Z, Spector TD, Wu Y-Z, Plass C, Esteller M. Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci U S A. 2005 Jul 11; [Epub ahead of print] Abstract

Comments on News and Primary Papers
Comment by:  Robert Peers
Submitted 20 December 2005
Posted 1 January 2006

The more knowledge we get on discordant twins, the better, especially in schizophrenia. Professor David Castle of Melbourne's Mental Health Research Institute once told me that the so-called "normal" twin is often, in fact, seen to have schizotypal personality.

There is an important lesson here that may shed light on the true nature of schizophrenia, which may be not a pure disease, but an aggravated form of schizotypy, in which differences in pre- and postnatal nutrition (for example) convert benign eccentricity into a serious psychotic illness.

People with mere schizotypy are odd, have magical thinking, can talk a lot, and can be intensely spiritual—character traits that may have been useful and appealing in primitive hunter-gatherer groups and early farming societies. Any overlap with bipolar traits would have added mental energy and leadership qualities as well. So there might be something good in schizotypy that has been given a bad name by schizophrenia.

Schizotypy that had not been converted into schizophrenia was probably common, but unnoticed, in Western populations prior to about 1770, when descriptions of typical psychosis, formerly rare, first became common, marking the onset of what Fuller Torrey calls the modern epidemic of insanity.

Schizotypy may also be more common in poorer nations, where not only is the prevalence of schizophrenia lower, due to much higher recovery rates than in the West, but recent data showing lower incidence rates as well suggest that schizotypy in those countries converts less often to schizophrenia, as in the pre-industrial era in the West. The reason for this is now thought to be lower saturated fat consumption in poorer nations, along with higher intake of essential fatty acids from plants and seafood.

If most "schizophrenia" genes are in fact schizotypy genes, and therefore do not directly cause schizophrenia, but only predispose to it, as twin discordance strongly suggests, then it should be possible to reduce the current high incidence of schizophrenia in Western peoples, by ensuring the healthiest possible maternal diet in pregnancy, and by promoting breastfeeding and optimum nutrition for the brain during early life.

Key nutrients would include neuroprotective omega-3 and omega-6 fatty acids and folate, while saturated fats should be restricted, since fatty pregnancy diet may cause the comorbid anxiety seen in a third of Western schizophrenia patients. As for epigenetic effects, folate deficiency and consequent homocysteine elevation may be leading causes of altered DNA methylation, both in utero and during postnatal life. Folate, in its tetrahydrofolate form, is also prone to destruction by the systemic oxidation caused by fatty diet, often eaten by overweight folate-resistant mothers.

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