Domain loss enables evolution of novel functions in a gene superfamily, including snake 3-finger toxins

3-finger toxins (3FTxs) are a functionally diverse family of toxins, seemingly unique to the venoms of caenophidian snakes. Although the ancestral function of 3FTxs is antagonism of nicotinic acetylcholine receptors (nAChR), redundancy conferred by accumulation of duplicate genes has facilitated extensive neofunctionalization, such that derived members of the family interact with a range of targets. 3FTxs are members of the Ly6/uPAR family, but their precise non-toxin ancestor remains unknown. Using a combination of traditional phylogenetic approaches, manual synteny analysis, and cutting-edge machine learning techniques, we have reconstructed a detailed evolutionary history of 3FTxs. We identify their immediate ancestor as a non-secretory Ly6, unique to squamate reptiles, and propose that changes in molecular ecology resulting from loss of a transmembrane region and changes in gene expression, paved the way for evolution of one of the most important families of snake toxins.