Abstract Objective Our primary objective was to investigate the variability of oxytocin (OT) and the GAMEN binding motif within the LNPEP oxytocinase in primates. Materials and Methods We sequenced the LNPEP segment encompassing the GAMEN motif in 34 Platyrrhini species, with 21 of them also sequenced for the OT gene. Our dataset was supplemented with primate sequences of LNPEP, OT, and the oxytocin receptor (OTR) sourced from public databases. Evolutionary analysis and coevolution predictions were made followed by the macroevolution analysis of relevant amino acids associated with phenotypic traits, such as mating systems, parental care, and litter size. To account for phylogenetic structure, we utilized two distinct statistical tests. Additionally, we calculated binding energies focusing on the interaction between Callithtrix jacchus VAMEN and Pro 8 OT. Results We identified two novel motifs (AAMEN and VAMEN), challenging the current knowledge of motif conservation in placental mammals. Coevolution analysis demonstrated a correlation between GAMEN, AAMEN, and VAMEN and their corresponding OTs and OTRs. Callithrix jacchus exhibited a higher binding energy between VAMEN and Pro 8 OT than orthologous molecules found in humans (GAMEN and Leu 8 OT). Discussion The coevolution of AAMEN and VAMEN with their corresponding OTs and OTRs suggests a functional relationship that could have contributed to specific reproductive and adaptive behaviors, including paternal care, social monogamy, and twin births, prominent traits in Cebidae species, such as marmosets and tamarins. Our findings underscore the coevolution of taxon‐specific amino acids among the three studied molecules, shedding light on the oxytocinergic system as an adaptive epistatic repertoire in primates.

From molecular variations to behavioral adaptations: Unveiling adaptive epistasis in primate oxytocin system