Evolutionary History and Functional Divergence of Hydroxycarboxylic Acid Receptors in Primates

Hydroxycarboxylic acid receptors are class A G-protein-coupled receptors that act as metabolic sensors linking cellular metabolic status to physiological and immune responses. This family comprises three members (HCAR1, HCAR2, and HCAR3), expressed in metabolically active tissues and immune cells. Here, we investigate the evolutionary history of the most recently derived members, HCAR2 and HCAR3, in primates. Phylogenetic analyses reveal a complex duplicative history involving multiple independent duplication events during ape evolution. As a result, most ape lineages harbor independently originated duplicated copies, whereas non-ape primates retain the ancestral single-copy condition (HCAR2/3). Functional inference indicates that this single-copy gene may be functionally similar to HCAR2, suggesting that the major functional innovation in apes is associated with the emergence of HCAR3. Gene expression analyses further show that major divergence in tissue expression occurred early, following the duplication that generated HCAR1 and the HCAR2/3 lineage, while HCAR2 and HCAR3 retain largely overlapping expression profiles. Together, our results suggest that HCAR3 receptors may have evolved repeatedly in apes, potentially contributing to refined lipid-sensing.