July 2005

Wired to Eat

Continued from page 1

By David Ewing Duncan

The Gene Hunters Arrive
In the summer of 1994, Rockefeller biomedical researchers first arrived on Kosrae, led by Friedman, director of the university's Starr Center for Human Genetics. The group set out to measure islanders' weight, height, and waist size; to collect information on the history of family diseases; and to perform a battery of tests, including measurements of cholesterol levels, blood sugar levels, and blood pressure.

In addition to finding that more than half of Kosraean adults were obese and 88 percent were overweight, the Rockefeller study also found that about 12 percent of the adult population had diabetes, compared with 8 percent in the United States. About 17 percent had hypertension, and 20 percent had high cholesterol. These rates are lower than those found in the United States, but they represent health problems that until recently were rare in Kosrae and the rest of the developing world. In a second round of tests, in 2001, the researchers also drew blood to be frozen and shipped back to New York, where they could extract the islanders' DNA to search for genes for obesity, heart disease, and diabetes.

The Rockefeller team chose Kosrae for its isolation, and because most of its people are descended from just a few families. The first Polynesians arrived 2,000 years ago. In the mid-19th century, European diseases and abuse reduced the islanders' numbers from several thousand to about 300. Having just a few genetic lineages on the island means that each person's genomic makeup is far more similar to his or her compatriots' than, say, an American's would be. "Looking for a gene is like searching for a needle in a haystack," says Friedman. "On Kosrae, the small gene pool makes the haystack smaller."

Friedman believes the Kosraeans' ballooning weight is a manifestation of what geneticist James Neel in 1962 dubbed the "thrifty gene" theory. Neel posited that in an environment prone to famine, hunter-gatherers gained a selective advantage if their genes predisposed them to storing fat when food was available. Those with such "thrifty genes" were more likely to survive famines and pass on their genes. But in modern times, the thrifty gene has proved a liability. The theory also posits that people who lived in early agricultural societies, such as those in the Fertile Crescent in the Middle East, had a steady supply of food from plants and domesticated animals and thus didn't need to store fat. So in our world today, people with lean genes are protected from obesity, and those with fat genes are at the mercy of DNA.

Friedman's search through the Kosraeans' genes recently became more precise with the use of a gene chip from Affymetrix, a Santa Clara, CA-based company. Researchers can use chips like Affymetrix's to scan genomes for differences in individual base pairs at specific locations -- variations known as single-nucleotide polymorphisms (SNPs) -- which can then be associated with differences in susceptibility to diseases such as obesity or diabetes. Friedman's team has joined with Affymetrix to run one of the first large-scale, genome-wide association studies, using the company's new 100,000-SNP chip to begin to analyze genetic differences among Kosraeans. This is a vast improvement over earlier chips that scanned 6,500 SNPs, according to Greg Yap, vice president of marketing at Affymetrix. "With the 100K chip, we get a much higher resolution across phenotypes," he says. "It's like GPS. Before, we could only see select parts of the world in a general way; now, you get great resolution in lots of places."

The gene-hunting effort is conducted in collaboration with a team at the Broad Institute, MIT and Harvard University's jointly operated center for genomic medicine. Led by David Altshuler, Broad's director of medical and population genetics, the researchers are about halfway through the SNP scanning process for the 2,000 Kosraean adults. The goal is to identify a library of SNPs that seem to correlate with the islanders' dispositions to be fat or lean. The researchers also hope to pinpoint patterns in the SNPs that will help support or refute the thrifty-gene theory.

Already, says Friedman, the preliminary data are pointing away from one of his theories -- that the lean people on Kosrae are descendants of Caucasians with Fertile Crescent genes who mated with locals who had thrifty genes. "Early evidence suggests that there are fewer Caucasian genes than we thought," explains Friedman. One possible explanation is that the genetics of something as important as appetite and eating would exhibit a great deal of diversity; that would guarantee that a population could adapt readily to different environmental conditions. In other words, the thrifty-gene theory might hold true even within a small, isolated population. "We'll be studying this more thoroughly in the coming months, looking for an explanation," says Friedman.