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

Abstract

AbstractOur study elucidates functional roles for conservedcis-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 theFat Mass & Obesity(Fto) locus. Some hibernation-linkedcis-elements in this TAD form regulatory contacts with multiple neighboring genes. Knockout mice for thesecis-elements exhibitFto, Irx3,andIrx5gene expression changes, impacting hundreds of genes downstream. Profiles of pre-torpor, torpor, and post-torpor phenotypes found distinct roles for eachcis-element in metabolic control, while a high caloric diet uncovered different obesogenic effects. Onecis-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 summaryDeletions of conservedcis-elements tied to hibernator evolution causes diverse metabolic traits in mice.