Genetic data from humans and hibernating animals has led to the discovery of over 300 potential master genetic switches that control obesity, according to a new study.
This provides new clues on genetic factors that may contribute to obesity and metabolic disorders.
The study, “Parallel Accelerated Evolution in Distant Hibernators Reveals Candidate Cis Elements and Genetic Circuits Regulating Mammalian Obesity,” was published in the journal Cell Reports.
Obesity is a major global problem. Yet in hibernating mammals, fat accumulation is key to survive cold and inactivity during winter.
The factors that influence the risk for obesity are complex. In fact, previous studies identified nearly 250 small regions of the genome and 123 genes that are associated with one’s susceptibility to become obese. The strongest genetic risk factor for human obesity is the Fat Mass and Obesity (FTO) gene region, particularly its non-coding regions — those that do not generate a protein.
A team from the The University of Utah assessed DNA sequences in people with Prader-Willi syndrome (PWS) — a major genetic cause of severe obesity in children — and hibernating mammals as a way to help explain the biological regulation of human obesity and metabolic disorders.
“Hibernators have evolved an incredible ability to control their metabolism,” Christopher Gregg, PhD, a co-author of the study, said in a university news story.
“Metabolism shapes risks for a lot of different diseases, including obesity, type 2 diabetes, cancer and Alzheimer’s disease. We believe that understanding the parts of the genome that are linked to hibernation will help us learn to control risks for some [of] these major diseases,” he said.
First, the researchers compared the genome of four hibernators that can be found worldwide: the thirteen-lined ground squirrel, little brown bat, gray mouse lemur, and the lesser Madagascar hedgehog tenrec.
Results showed small, non-coding DNA sequences in the four species. Though different, these regions — called parallel accelerated regions (pARs) — could also be found within the human genome, primarily located near genes associated with obesity, including the FTO sequence. pARs had been previously associated with the regulation of cancer and mutation resistance by the same team.
“A big surprise from our new study is that these important parts of the genome were hidden from us in 98 percent of the genome that does not contain genes — we used to call it ‘junk DNA’,” Gregg said.
The researchers then examined available genetic information from people with PWS and healthy controls.
Results indicated that 51 genes linked to PWS had pARs in close proximity. Overall, the team identified 364 genetic sequences that likely play a role in the regulation of obesity, as they were located near 114 obesity susceptibility genes.
“Our results show that hibernator accelerated regions are enriched near genes linked to obesity in studies of hundreds of thousands of people, as well as near genes linked to a syndromic form of obesity,” said Elliot Ferris, first author of the study.
Based on their findings, the scientists think that hibernators developed ways to “turn off” DNA sequences that control the activity of obesity genes.
“Our findings provide foundations to functionally dissect the noncoding regulatory mechanisms controlling obesity and hibernation,” the scientists stated.
Future studies may provide better understanding of how to control obesity risks in humans. Currently, the team is testing the discovered pARs in mice using a modified CRISPR genome editing strategy.
“Since obesity and metabolism shape risks for so many different diseases, the discovery of these parts of the genome is a really exciting insight that lays foundations for many important new research directions,” Gregg said.
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