Chemical modifications to DNA may affect the activity of key genes involved in regulating body weight, a study finds, raising the possibility that scientists could discover environmental factors beyond calorie intake and exercise that influence a person’s size.
The study, published September 15 in Science Translational Medicine, is also the first to demonstrate that these chemical modifications to DNA are unique to an individual and may affect a person’s risk of developing common diseases. Referred to as epigenetic, these changes don’t alter the DNA sequence itself but the way genes are turned on and off.
Studying epigenetic marks may help scientists learn more about the causes of disease, says Michael Skinner, an epigenetics researcher at Washington State University in Pullman who was not part of the new study. “There’s a great deal of disease that is directly influenced by the environment that today we can’t explain just using genetics,” he says.
In the study, researchers from Johns Hopkins University mapped one type of epigenetic change known as methylation in DNA samples taken 11 years apart from 74 Icelandic people. Methylation generally has the effect of turning off nearby genes.
The team surveyed about 4.5 million spots on the genome of each person and determined how much of the DNA at each location carried marks of methylation. The amount of methylation varied among people at 227 of those spots, dubbed variably methylated regions or VMRs. Each person had a unique combination of these regions.
Of the 227 variably methylated regions, 119 had the same amount of methylated DNA both times they were measured. Other VMRs changed over the 11-year period, presumably as nongenetic factors such as diet, age and chemical exposures varied.
Andrew Feinberg, a geneticist at Johns Hopkins who led the study, is a proponent of the idea that epigenetic changes can lead to disease. To determine whether the methylation signatures found in the Icelandic people are associated with disease, the team compared the amount of methylated DNA at each of the stable VMRs — those in which methylation did not change over time — with each person’s body mass index.
The team found four variably methylated regions at which more methylated DNA correlated with larger body mass. Obese people had more heavily methylated DNA at those regions than did people of normal weight. The four VMRs are in or near genes that have previously been linked to obesity or diabetes.
One of the genes, called PRKG1, has been shown to be involved in foraging behavior in nematodes. “You can’t help but wonder whether it also sends you to the refrigerator,” Feinberg says.
The researchers don’t know whether the epigenetic marks help cause obesity or are a side effect of weighing more. But future studies like the Feinberg study may show scientists how genes and the environment interact to determine disease risk.
“As a concept, it’s a very full road map for those researchers who want to study complex diseases that may have an epigenetic component,” says Schahram Akbarian, a neuroscientist at the University of Massachusetts Medical School in Worcester. Genetic studies have failed to fully explain a person’s risk of getting a disease, and Akbarian wonders whether epigenetic studies will fare better. “If they can really deliver is another question,” he says.
