Parallel Accelerated Evolution in Distant Hibernators Reveals Candidate Cis Elements and Genetic Circuits Regulating Mammalian Obesity

Abstract

Summary: Obesity is a clinical problem and an important adaptation in many species. Hibernating mammals, for example, become obese, insulin resistant, and hyperinsulinemic to store fat. Here, we combine comparative phylogenomics with large-scale human genome data to uncover candidate cis elements regulating mammalian obesity. Our study examines genetic elements conserved across non-hibernating mammals to identify genome-wide patterns of accelerated evolution in hibernators from different clades. The results reveal the existence of parallel accelerated regions (pARs) in distant hibernators. Hibernator pARs are disproportionately located near human obesity susceptibility genes compared to random conserved regions, hibernator ARs that are not parallel, and non-hibernator pARs. We found 364 candidate obesity-regulating cis elements and genetic circuits in different cell types. The Fat Mass and Obesity (FTO) locus, the strongest genetic risk factor for human obesity, is an enriched site for hibernator pARs. Our results uncover noncoding cis elements with putative roles in obesity and hibernation. : Obesity is a clinical problem but also an important adaptation in hibernators. By using comparative genomics approaches to analyze the genomes of hibernators from different clades and contrasting the results with human obesity risk loci, Ferris and Gregg found 364 conserved cis elements with putative roles in regulating obesity and hibernation. Keywords: obesity, hibernation, comparative genomics, accelerated evolution, regulatory elements, gene regulation, epigenetics