Genomic Convergence in Hibernating Mammals Elucidates the Genetics of Metabolic Regulation in the Hypothalamus

Extreme metabolic adaptations can enable understanding of the genetic programs governing mammalian metabolism. Here we used convergent evolutionary changes in hibernating lineages to define conserved cis-regulatory elements (CREs) and programs for metabolic control. We characterized gene expression and chromatin dynamics in the mouse hypothalamus across fed, fasted, and refed states, then used comparative genomics of hibernating versus non-hibernating lineages to identify cis-elements with convergent changes in hibernators. Multi-omics approaches pinpointed CREs, hub genes, regulatory programs, and cell types underlying lineage divergence. Hibernators accumulated loss-of-function effects for CREs regulating hypothalamic responses, and the refeeding period after fasting served as a key phase for molecular processes with convergent evolutionary changes. Together, this work provides a genetic framework for harnessing hibernator adaptations to understand human metabolic control.