Adaptive evolution at thyroid hormone, insulin and glycerolipid pathways improved energy metabolism in high-latitude Eurasian populations

High-latitude populations represent valuable case studies to investigate the genetic bases of human biological adaptations to cold climates. Nevertheless, by relying on traditional natural selection models, a limited fraction of them was identified. To overcome this issue, we integrate diverse inferential methods in the attempt to pinpoint combinations of genes presenting both selection signatures and functional relationships supporting their synergic role in regulating a biological trait, as expected under polygenic adaptation. We analyze Yakut genomes from Northeastern Siberia and Russian ones, pointing to adaptive evolution at genes contributing to functions modulated during cold exposure, such as thyroid hormone/insulin signalling (THRB, RCAN2, INSR, NFKB1), brown adipose tissue differentiation (ERBB4) and glycerolipid metabolism (GPAT3). Concerted changes at these loci may support enhanced heat production and responsiveness to insulin, having been partly influenced also by Neanderthal introgression, and provide suggestive insights into the complex adaptations that enabled Eurasians' ancestors to colonize cold environments.