The evolutionary and domestication processes have shaped the sequences of neuropeptide prohormone genes that mediate cell–cell communication, affecting a wide range of biological systems dependent on neuropeptide signaling. Understanding these modifications helps explain physiological contrasts between domesticated Cetartiodactyla, including cattle, pigs, and llamas, and their wild counterparts such as hippopotamuses, giraffes, and whales. A systematic investigation was carried out to assess how evolutionary and domestication pressures influenced neuropeptide prohormone proteins, which are precursors of active neuropeptides. Genomic data from 118 Cetartiodactyla species, representing 22 families, were screened for 98 neuropeptide prohormone genes. Among suborders, Ruminantia retained PYY2 while losing RLN1. Alterations in the sequences of GNRH2, IAPP, INSL6, POMC, PRLH, and TAC4 may have led to the absence of certain functional neuropeptides in some lineages. Evolutionary modeling indicated that most neuropeptide prohormone genes tend to resist amino acid substitutions introducing bulky or hydrophobic residues. Notably, variations distinguishing wild and domestic species were linked to molecular mechanisms involved in “fight or flight” regulation. Overall, the findings emphasize the necessity of comparing neuropeptide prohormone gene repertoires among both closely and distantly related species. These results strengthen the groundwork for further functional studies of the neuropeptidome relevant to health, behavioral adaptation, and animal production.
