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Study Finds Weight Influenced by Thousands, Not Hundreds, of Genes

NEW YORK (GenomeWeb News) – A new study suggests that more than 6,000 genes influence body weight in mice, leading researchers to speculate that the genetics of human obesity may be similarly complex.
Using information gleaned from the Jackson Laboratory Mouse Genome Database, researchers at Philadelphia’s Monell Chemical Senses Center investigated the effect of gene knockouts on mouse body weight.
Their results, published online in BMC Genetics on January 8th, suggest that thousands of genes influence body weight in mice — with ten times more genes associated with weight gain than weight loss. The research has implications not only for those studying diseases in mice but also for those interested in controlling weight in humans.
“The surprise is just how many genes are involved,” Michael Tordoff, a behavioral geneticist at Monell and an author of the paper, told GenomeWeb Daily News today. He said that researchers previously thought that the number of genes regulating weight was in the order of hundreds.
About 10 percent of known mouse genes have been knocked out and a great deal of information about these knockouts — including weight trends — is housed in the MGD. Lead researcher Danielle Reed and her colleagues surveyed nearly 2,000 viable knockout strains for which weight information was available, classifying the knockouts into three categories: normal size, lighter and smaller, or larger and heavier.
More than a third of the knockout mice weighed less than controls. In contrast, about three percent weighed more. By extrapolating these results to the entire mouse genome, the researchers predicted that more than 6,000 genes — roughly a quarter of the genome — actually influence mouse body weight.
Concerned that weight information was included in the database more often when there were weight changes than when there weren’t, Reed and her colleagues contacted dozens of researchers who had not entered weight information and asked them about weight patterns in their knockout mice. Data gathered using this approach gave similar results to those obtained from the database alone.
Since non-viable knockouts were excluded from analysis, and because mice were typically fed controlled diets, Tordoff believes this is the “absolute lowest” estimate for genes involved in mouse body weight.
“Body weight is highly heritable, and numerous quantitative loci have been mapped in mice,” the authors noted, “but ‘multigenic’ is an insufficient term for the thousands of loci that could contribute to this complex trait.”
If, as the study suggests, body weight is altered in a third of viable mouse knockouts, the finding may complicate animal research since body weight may influence other conditions being investigated with the knockout approach. Similarly, Tordoff said, the findings may affect those doing quantitative trait loci research, since there is a one in three chance of seeing a weight effect no matter what gene is targeted during QTL.
Although the results were obtained from an animal model, Tordoff believes human weight patterns are just as complicated, making him skeptical about the feasibility of developing human weight loss therapeutics based on genetic studies. With thousands of candidate genes, he noted, it may be impossible to know which genes to target, if any.
“What is the main mechanism controlling body weight?” Tordoff asked. “There isn’t one, really.”

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