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

Extreme metabolic adaptations can elucidate genetic programs governing mammalian metabolism. Here we used convergent evolutionary changes in hibernating lineages to define conserved cis-regulatory elements (CREs) and metabolic programs. We characterized mouse hypothalamus gene expression and chromatin dynamics 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. This work provides a genetic framework for harnessing hibernator adaptations to understand human metabolic control. Convergent signals define cis-regulatory mechanisms behind food scarcity responses and hibernator-homeotherm divergence.