Concerted evolution reveals co-adapted amino acid substitutions in Na+K+-ATPase of frogs that prey on toxic toads

Curr Biol. 2021 Jun 21;31(12):2530-2538.e10. doi: 10.1016/j.cub.2021.03.089. Epub 2021 Apr 21.


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 although 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.

Keywords: ATP-alpha subunit; cardiotonic steroids; epistasis; gene duplication; molecular evolution; natural selection; neofunctionalization; non-allelic gene conversion; potassium ATPase; sodium; toxin resistance.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adaptation, Physiological* / genetics
  • Amino Acid Substitution*
  • Animals
  • Anura / genetics
  • Anura / physiology*
  • Bufonidae
  • Eating*
  • Evolution, Molecular*
  • Gene Conversion
  • Gene Duplication
  • Predatory Behavior*
  • Sodium-Potassium-Exchanging ATPase / chemistry*
  • Sodium-Potassium-Exchanging ATPase / genetics*
  • Sodium-Potassium-Exchanging ATPase / metabolism


  • Sodium-Potassium-Exchanging ATPase