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June, 2007
Obesity: A Link to Rare Gene Variations

Sometimes, the rarest of the rare can still have an impact. A multi-institutional team of scientists led by Berkeley Lab geneticist Len Pennacchio has found that extremely uncommon gene variations likely contribute to obesity.

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Len Pennacchio (Photo Roy Kaltschmidt, CSO)

How and why — and to what extent — remain a mystery, but the research adds another clue to the problem of obesity, which is reaching epidemic proportions in developed nations. Overeating and lack of exercise loom as the chief culprits. But heredity and gene defects are implicated too, and now scientists have a better understanding of their role.

Specifically, Pennacchio's team studied 58 genes in 379 obese and 378 lean people from Ottawa, Canada. These genes — a small fraction of a human's 25,000 genes — were chosen because evidence suggests they may be involved in processes that regulate body weight, such as appetite. Half the people in the study group were fatter than 95 percent of the general population. The other half were thinner than 90 percent of the population.

"We observed that the obese subjects had twice as many rare gene variants that alter the predicted protein sequence, compared to the lean subjects," says Pennacchio, a geneticist with Berkeley Lab's Genomics Division and head of the Genetic Analysis program at the Department of Energy's Joint Genome Institute (JGI). "This suggests a link between such changes and weight status."

The team focused on the extreme ends of the population spectrum because they are likely to be enriched with whatever genetic quirks contribute to obesity and thinness. By comparing the two groups, the rare but important variants that promote obesity should stand out — if they exist.

This needle-in-a-haystack search is made possible by an innovative genetic sleuthing technique called resequencing, a standard tool geneticists use to search for gene mutations that may influence an organism's traits. Scientists have long used the method to research single gene disorders, such as cystic fibrosis. Now, with the development of a whole-human-genome reference sequence, and with decreasing sequencing costs, the technique has been scaled up at the JGI to help scientists understand more complex and common conditions such as obesity.

Using this approach, the team read out the sequences of all 58 genes from each of the 757 study participants, and then analyzed the data for telltale differences among individuals. They found 1,074 genetic variants, with most of these variants so rare that they were found in less than one percent of the participants.

They also found twice as many rare variants in the obese group compared to the lean group. Although this is more than is expected by chance, Pennacchio adds that they haven't proved anything: the results only suggest that rare variants potentially contribute to increased weight. In addition, the team did not find that the same rare variants perfectly tracked with weight status in families, which is another indication of obesity's complex underpinnings.

"Our argument is that these variants do have some effects, but the effects are relatively small, and they don't on their own cause obesity," says Pennacchio. "In other words, these variants are enriched in the obese population compared to the lean, but it is only a part of the puzzle. It is likely that these susceptibility variants work in concert with other genomic variants to determine an overall body-weight metabolism, with some variants pulling the weight teeter-totter toward lean and other variants toward obesity."

The work also helps pave the way for unrelated but equally important research. Specifically, JGI's resequencing pipeline is being applied to bioenergy research. Scientists are using the technique to understand the genetic makeup of poplar trees, with the goal of possibly optimizing these trees for use as an efficient feedstock for ethanol production. Equipped with a poplar genome reference sequence, JGI scientists can work to determine what genes contribute to favorable traits such as fast growth and disease resistance, and then select these genes to improve biofuel feedstocks.

"This obesity research is a proof of principle. We can apply the same paradigm to search for interesting genetic variants in the poplar or other plant-based biofuels," says Pennacchio.

Pennachio's colleagues on the obesity research are Nadav Ahituv and Wendy Schackwitz of Berkeley Lab's Genomics Division; Nihan Kavaslar, Sybil Hébert, Heather Doelle, Robert Dent, and Ruth McPherson of the University of Ottawa; Baran Ersoy and Christian Vaisse of the University of California at San Francisco; Gregory Kryukov, Steffen Schmidt, and Shamil Sunyaev of Brigham and Women's Hospital and Harvard Medical School; Nir Yosef, Eytan Ruppin, and Roded Sharan of Tel Aviv University; and Jonathan Cohen of the University of Texas Southwestern Medical Center. Pennachio, Ahituv, Schackwitz, Anna Ustaszewska, and Joel Martin are with the DOE Joint Genome Institute. 

Additional information

  • "Medical sequencing at the extremes of human body appears," by Nadav Ahituv, Nihan Kavaslar, Wendy Schackwitz, Anna Ustaszewska, Joel Martin, Sybil Hébert, Heather Doelle, Baran Ersoy, Gregory Kryukov, Steffen Schmidt, Nir Yosef, Eytan Ruppin, Roded Sharan, Christian Vaisse, Shamil Sunyaev, Robert Dent, Jonathan Cohen, Ruth McPherson, and Len A. Pennacchio appears in the April, 2007 issue of the American Journal of Human Genetics.
  • More about Len Pennacchio's research