BioEd Online

Researchers have used a new technique to hunt for rare genetic quirks that explain why some people are extremely fat or very thin.

The researchers, led by Len Pennacchio of the Lawrence Berkeley National Laboratory in California, studied 757 Canadians from Ottawa. Half of the participants were chosen because they were fatter than 95 of the general population for their height: on average they weighed 125 kilograms. The other half was thinner than 90% of the population, with a mean weight of 57 kilograms.

The team examined 58 genes known to be related to obesity, appetite, or the conversion of food into energy, in every participant. They looked for tiny differences between people in the series of chemical building blocks that make up each gene. This technique, called medical sequencing or resequencing, aims to discover rare genetic variations that may subtly influence particular traits — including body size.

Most previous genetic trawls have focused on using the HapMap — a catalogue of common genetic variants shared by most people with a certain disease. Resequencing is different, as it looks for genetic quirks that are unique to just a few individuals. Resequencing studies have been used to find variations that may cause cancer¹ and differences in cholesterol², whereas HapMap studies have been used to hunt for more common variations that contribute to a range of conditions, including diabetes (see 'Broad sweep of genome zeroes in on diabetes').

Small pieces of the puzzle

Pennacchio's team found 1,074 genetic variants in the sequenced genes, they report in the American Journal of Human Genetics³. Most of these variants were rare, meaning they were found in less than 1% of the study participants. The fat participants had significantly more variation in the genes known to be linked to severe obesity. But when the team looked for the same rare variants in family members of the affected participants, they couldn't link the genetic difference directly to body size. So each variant on its own isn't enough on its own to make a person fat or thin.

"Obesity is such a complex condition — it's not a black-and-white thing — so it doesn't mean these genes might not contribute to weight differences, it just says they're not clearly causative on their own," Pennacchio says.

Scientists are unsure how much rare and common genetic variants contribute to disease, especially in complex disorders such as obesity, which are caused by multiple environmental and inherited factors. And it is proving hard to pin down — at least for now. Resequencing studies are more difficult and expensive than HapMap studies, so fewer scientists have done them.

"We could show that there are rare variants that have a significant difference between obese and lean subjects, but even with the amount of sequencing we've done, we can only scratch the surface," Pennacchio says.

As the cost of resequencing studies drops, Pennacchio predicts that the problem will be cracked. "This is going to be a big growth area for the field."