Conserved Noncoding Cis-Elements Associated with Hibernation Modulate Metabolic and Behavioral Adaptations in Mice

Our study elucidates functional roles for conserved cis- elements associated with the evolution of mammalian hibernation. Genomic analyses found topologically associated domains (TADs) that disproportionately accumulated convergent genomic changes in hibernators, including the TAD for the Fat Mass & Obesity ( Fto ) locus. Some hibernation-linked cis- elements in this TAD form regulatory contacts with multiple neighboring genes. Knockout mice for these cis- elements exhibit Fto, Irx3, and Irx5 gene expression changes, impacting hundreds of genes downstream. Profiles of pre-torpor, torpor, and post-torpor phenotypes found distinct roles for each cis- element in metabolic control, while a high caloric diet uncovered different obesogenic effects. One cis- element promoting a lean phenotype influences foraging behaviors throughout life, affecting specific behavioral sequences. Thus, convergent evolution in hibernators pinpoints functional genetic mechanisms of mammalian metabolic control. One-sentence summary Deletions of conserved cis- elements tied to hibernator evolution causes diverse metabolic traits in mice.