Metabolomics-Guided Genomic Comparisons Reveal Convergent Evolution of Hibernation Genes in Mammals.

Hibernation exists in several unrelated mammalian lineages, allowing animals to survive extreme 0environmental conditions through profound physiological shifts, including reduced metabolic rate, heart rate, respiration, and body temperature. These physiological shifts allow hibernators to rely solely on fat reserves, simultaneously avoiding the adverse effects of prolonged immobility seen in nonhibernating species. Although research on individual species has highlighted key aspects of these adaptations, the genetic basis of hibernation across mammals remains poorly understood. Synthesizing both single species and comparative approaches, we use metabolomic data from waking and hibernating black bears (Ursus americanus) to guide bioinformatic analyses of genes using tests of selection and evolutionary rate convergence across independent lineages of hibernating mammals. Our analyses reveal significant changes in carnitine levels between states. Using public databases, we generate candidate genes which may contribute to regulation of carnitine, and use these to test for signatures of selection across several independent lineages of hibernating mammals. We also utilize a dataset of 19k proteins across 120 mammalian genomes to identify genes evolving at convergent rates across hibernating mammals. Using both approaches, we find several novel genes likely to impact carnitine metabolism and related functions vital to hibernation such as metabolic shifts, oxidative stress, and tissue preservation. These findings provide new insights into the genetic basis of hibernation and offer promising targets for translational research, including the development of clinical therapies that mimic hibernation-like states for applications in medicine and space exploration.