Structural permissivity of the oxytocin receptor as a potential contributor to oxytocin pathway evolvability in New World monkeys

The oxytocinergic system is a key modulator of social behavior, including traits associated with social monogamy. However, it remains unclear whether amino acid variation in oxytocin (OT) and its receptor (OTR) contributes to behavioral divergence between monogamous and non-monogamous primates. We analyzed variation in the OXT and OXTR genes across 249 and 238 primate species, respectively, integrating phylogenetic models, comparative statistical analyses, and machine-learning approaches. While both genes show limited evidence of a direct association with social monogamy across primates, patterns within Platyrrhini suggest an alternative evolutionary scenario. In this clade, OTR exhibits characteristics consistent with a more permissive binding scaffold, potentially allowing multiple OT variants to be tolerated without compromising core signaling function. Two fixed TM4 substitutions, Ala169Val and Val172Met, flank the ligand-interacting residue Gln171, potentially remodeling the binding pocket. Stability predictions indicate an epistatic effect in the double mutant that increases structural robustness, consistent with models in which elevated stability buffers destabilizing variation and enhances evolvability. We propose the testable hypothesis that oxytocinergic diversification in New World monkeys may have been facilitated by a permissive OTR scaffold, shifting the focus from direct genotype–behavior correlations toward structural conditions that may contribute to the emergence of complex social phenotypes.