When it comes to our expanding waistlines, we usually blame either diet or genes. But a new study fingers a third culprit: chemicals that attach to DNA and change its function. A survey of millions of these modifications has uncovered a handful associated with body mass index, a measure of height and weight. Although the findings don't prove that the modifications cause obesity, they may one day help doctors better predict who should be counting their calories.
The chemicals in question are known as methyl groups, and they act a bit like volume knobs on our DNA. They can turn the activity of a gene up or down, and even on and off. Some of these modifications—known as epigenetic changes—are inherited; some are acquired throughout life. Only in the past 5 years have researchers begun to comprehensively map which DNA sequences in a person are methylated.
At Johns Hopkins University School of Medicine in Baltimore, Maryland, M. Daniele Fallin, Andrew Feinberg, and their colleagues decided to build large-scale maps of such "epigenomes." Their goal was to see whether epigenomes varied from person to person, like fingerprints do, and whether the pattern of chemical modifications was stable in an individual throughout his or her life. Using innovative technology developed in Feinberg's lab, the researchers took DNA samples from 74 Icelanders and in each examined 4.5 million places along the human genome where methylation can occur. The Icelandic people are part of a long-term study in which their health status and white blood cells have been collected regularly since 1967. "The scale of this [epigenetics] study is unprecedented," says Kun Zhang, a genome technology researcher at the University of California, San Diego.
The team found 227 DNA regions with different methylation patterns from person to person. Of those, 119 remained the same over the decade within each person, providing an epigenetic fingerprint for each individual, the researchers report today in Science Translational Medicine. Many people expect methylation patterns to be constantly changing. "To find so many sites of methylation that were consistent over time was kind of surprising," Feinberg says.
Next, the team looked to see whether any of the methylated DNA correlated with body mass index. Thirteen did. With some genes, the higher the body mass index, the greater the methylation; with other DNA sequences, the reverse was true. Four of the 13 methylation patterns remained the same between 1991 and 2002 in the individuals examined. Among the 13 methylation sites, about half harbored genes that have previously been linked to or were suspected of contributing to obesity or diabetes. Other genes highlighted by the methylation study, such as one involved with foraging behavior in rodents, were a surprise. Still, says Feinberg, "it's too soon to say if [the methylation fingerprint] is predictive of disease."
Geneticist Carmen Sapienza of Temple University School of Medicine in Philadelphia, Pennsylvania, is optimistic, however. To date, genes identified as associated with obesity and other common diseases have not been very useful for assessing who is most at risk or for developing new treatments because each gene has such a small influence on disease risk. But adding in these epigenetic fingerprints might help make genetic information more predictive, he points out. If validated, notes Zhang, these patterns could "allow at-risk individuals to adjust diet or lifestyle to control their weight."