Concerted evolution reveals co-adapted amino acid substitutions in frogs that prey on toxic toads

Although gene duplication is an important source of evolutionary innovation, the functional divergence of duplicates can be opposed by ongoing gene conversion between them. Here we report on the evolution of a tandem duplication of Na + ,K + -ATPase subunit α1 (ATP1A1) shared by frogs in the genus Leptodactylus , a group of species that feeds on toxic toads. One ATP1A1 paralog evolved resistance to toad toxins while the other retained ancestral susceptibility. Within species, frequent non-allelic gene conversion homogenized most of the sequence between the two copies, but was counteracted by strong selection on 12 amino acid substitutions that distinguish the two paralogs. Protein-engineering experiments show that two of these substitutions substantially increase toxin resistance, whereas the additional 10 mitigate their deleterious effects on ATPase activity. Our results reveal how examination of neo-functionalized gene duplicate evolution can help pinpoint key functional substitutions and interactions with the genetic backgrounds on which they arise. In the frog genus Leptodactylus , a duplication of ATP1A1 has evolved toxin-resistance. Using evolutionary and functional analyses, Mohammadi, Yang, Harpak et al. exploit a conflict between gene conversion and selection to identify amino acid substitutions underlying toxin-resistance and maintaining the functional integrity of the resistant paralog.