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

Shabnam Mohammadi, Lu Yang, Arbel Harpak, Santiago Herrera-Álvarez, María del Pilar Rodríguez-Ordoñez, Julie Peng, Karen Zhang, Jay F. Storz, Susanne Dobler, Andrew J. Crawford, Peter Andolfatto

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)2530-2538.e10
JournalCurrent Biology
Issue number12
StatePublished - Jun 21 2021
Externally publishedYes


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

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)


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