Reconstructing the Origins of a Neuropeptide Signaling System Using the Accelerated Evolution of Biodiverse Cone Snail Venoms

Somatostatin and its related peptides (SSRPs) form an important family of hormones with diverse physiological roles. The ubiquitous presence of SSRPs in vertebrates and several invertebrate deuterostomes suggests an ancient origin of the SSRP signaling system. However, the existence of SSRP genes outside of deuterostomes has not been established and the evolutionary history of this signaling system remains poorly understood. Our recent discovery of SSRP-like toxins (consomatins) in venomous marine cone snails (Conus) suggested the presence of a homologous signaling system in mollusks and potentially other protostomes. Here we identify the molluscan SSRP-like signaling gene that gave rise to the consomatin family. Following recruitment into venom, consomatin genes experience strong positive selection and repeated gene duplications resulting in the formation of a hyper-diverse family of venom peptides. Intriguingly, the largest number of consomatins was found in worm-hunting species (> 400 sequences), indicating a homologous system in annelids, another large protostome phylum. Comprehensive sequence mining enabled the identification of orthologous SSRP-like sequences (and their corresponding orphan receptor) in annelids and several other protostome phyla. These results establish the existence of SSRP-like sequences in many major branches of bilaterians, including xenacoelomorphs, a phylum believed to have emerged before the divergence of protostomes and deuterostomes, ~ 600 My ago. Finally, having a large set of predator-prey SSRP sequences available, we show that while the cone snails signaling SSRP-like genes are under purifying selection, in striking contrast, the consomatin genes experience rapid directional selection to target receptors in a changing mix of prey.