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Their epigenomes are different // Thus their disease risks are different // Studies of which could benefit twins and non-twins alike

Same Genes, Different Fates

By Timothy Gower // Photographs by Martin Schoeller / August // Fall 2013
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Pair of older twins

Martin Schoeller / August

Eppie Lederer and Pauline Phillips were one of the most famous pairs of identical twins in the United States during the 20th century. Born 17 minutes apart, both women became wildly popular syndicated columnists—as Ann Landers and Abigail Van Buren, respectively—and dispensed tart-tongued advice about love and other matters. Photos from their younger days reveal that the two women were uncanny look-alikes, both graced with fashion-model cheekbones and vibrant eyes.

Over the years, ever-changing hairstyles made it easier to tell them apart. But it was their dramatically diverging health, finally, that truly distinguished one from the other. Eppie died of multiple myeloma at age 83, while Pauline lived to be 94 before succumbing to Alzheimer’s disease this year. That may seem surprising—after all, as identical twins they have perfectly matched DNA. But it turns out that twins have rates of “disease discordance”—that is, if one has a medical condition, the other twin typically won’t get it—that are well over 50% for most conditions.

Yet if DNA is not destiny, how is it that genes and environmental influences interact to bring about disease? Part of the answer may come from the burgeoning study of epigenetics. Developmental biologist Conrad Waddington is credited with coining the term in the 1940s, and even today there is disagreement among scientists about how to define it. There is, however, agreement that humans and animals have a chemical infrastructure—an epigenome—that switches genes on and off. (The prefix epi derives from the Greek, meaning “over” or “above.”) Evidence suggests that environment and lifestyle choices can trigger epigenetic modifications, and that could help explain why identical twins end up being not so identical.

Tinkering with gene switches can have a profound effect on how they behave, and labs around the world are now scanning the genome in hopes of identifying epigenetic modifications—sometimes called “marks” or “tags”—that could serve as biomarkers, helping to predict and identify a wide range of conditions. Drug developers, meanwhile, are exploring compounds that may be capable of thwarting epigenetic modifications that cause key genes to become under- or overactive, thereby promoting cancer and other diseases. Several medications that work by altering the epigenome are already in use.

And in all of this, identical twins are increasingly seen as desirable study subjects; because their genomes are the same, eliminating one essential variable, differences in their epigenomes might offer clues to the molecular origins of disease. “Epigenetics provides the mechanistic link between nature and nurture,” says molecular biologist Nessa Carey, author of The Epigenetics Revolution.

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1. “Epigenetic Differences Arise During the Lifetime of Monozygotic Twins,” by Mario F. Fraga et al., Proceedings of the National Academy of Sciences, July 2005. Fraga and colleagues found evidence of significant epigenetic “drift” in middle-aged identical twins, which some believe helps explain their frequent “disease discordance.”

2. “A Twin Approach to Unraveling Epigenetics,” by Jordana T. Bell and Tim D. Spector, Trends in Genetics, March 2011. Over the last few years, a number of review articles have made the case that identical twins are the ideal model for examining the link between epigenetics and disease. Here, Bell and Spector argue that twin studies are “considerably more powerful discovery tools than studies on singletons” for the epigeneticist.

3. The Epigenetics Revolution: How Modern Biology Is Rewriting Our Understanding of Genetics, Disease, and Inheritance, by Nessa Carey, Columbia University Press, 2012. An enthusiastic but clear-eyed overview of the field of epigenetic.

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