Origin and convergent evolution of exendin genes

Exendins are secretin hormone-like peptides that are components of the toxins from two venomous lizards, Heloderma suspectum (Gila monster) and Heloderma horridium (Mexican bearded lizard). Exendins-1 and -2 are vasoactive intestinal peptide (VIP)-like, both in sequence and function, while exendins-3 and -4 are glucagon-like peptide-1 (GLP-1)-like. The evolutionary origin of these peptides, and the genes that encode them, has been unclear. Recently, genes orthologous to exendin have been identified in reptiles, birds and amphibians. Analysis of the orthologous sequences demonstrates that the Heloderma exendins diversified by gene duplication from a common exendin ancestor on the Heloderma lineage after divergence from other reptiles, including the anole lizard and Burmese python. In addition, the exendin toxin peptide sequences, but not their pro or signal peptides, have evolved very rapidly on the Heloderma lineage, likely as they adapted to their new function as toxins. Exendins-1 and -2 not only evolved rapidly but their sequences have evolved convergently upon that of VIP, resulting in a doubling of its identity with VIP, while exendins-3 and -4 have retained an ancestral property of being more GLP-1-like sequences. These results suggest that the ancestral role of exendin, which is potentially still retained in some species, had greater similarity with proglucagon-derived peptides or GIP.

► We examine the origin of the Heloderma exendin toxin genes.
► Exendin orthologs are found in diverse vertebrates. > Exendin toxins diverged on the Heloderma lineage.
► Exendin toxins from Heloderma, in contrast to non-Heloderma exendins evolve rapidly.
► Exendins-1 and -2, but not -3 and -4, have evolve by convergent evolution.