@article{d9e936b7d5be43aeb5a71828f88c3ecc,
title = "Concerted evolution reveals co-adapted amino acid substitutions in Na+K+-ATPase of frogs that prey on toxic toads",
abstract = "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",
author = "Shabnam Mohammadi and Lu Yang and Arbel Harpak and Santiago Herrera-{\'A}lvarez and {del Pilar Rodr{\'i}guez-Ordo{\~n}ez}, Mar{\'i}a and Julie Peng and Karen Zhang and Storz, {Jay F.} and Susanne Dobler and Crawford, {Andrew J.} and Peter Andolfatto",
note = "Funding Information: We thank M. Przeworski for helpful comments on the manuscript. We thank C. Natarajan, K. Rohlfing, V. Wagschal, and P. Kowalski for assistance in the laboratory. Thanks to M. Lyra for help in resolving issues of Leptodactylus taxonomy. This study was funded by grants to P.A. from the National Institutes of Health ( R01-GM115523 ) and to J.F.S. from the National Institutes of Health ( R01-HL087216 ) and the National Science Foundation ( OIA-1736249 ), to S.D. from Deutsche Forschungsgemeinschaft (DFG) (grant DO527/10-1 ), and a fellowship to A.H. from The Simons Foundation{\textquoteright}s Society of Fellows (no. 633313 ). Funding Information: We thank M. Przeworski for helpful comments on the manuscript. We thank C. Natarajan, K. Rohlfing, V. Wagschal, and P. Kowalski for assistance in the laboratory. Thanks to M. Lyra for help in resolving issues of Leptodactylus taxonomy. This study was funded by grants to P.A. from the National Institutes of Health (R01-GM115523) and to J.F.S. from the National Institutes of Health (R01-HL087216) and the National Science Foundation (OIA-1736249), to S.D. from Deutsche Forschungsgemeinschaft (DFG) (grant DO527/10-1), and a fellowship to A.H. from The Simons Foundation's Society of Fellows (no. 633313). P.A. and A.J.C. conceived of and oversaw the project; L.Y. M.d.P.R.-O. S.H.-?. J.P. and A.J.C. collected samples and generated sequence data; L.Y. A.H. P.A. S.H.-?. and K.Z. performed evolutionary and population genetics analyses; S.M. J.F.S. S.D. A.J.C. and P.A. designed functional experiments; S.M. and P.A. performed experiments and associated statistical analyses; S.M. J.F.S. L.Y. A.H. and P.A. wrote the paper; and all authors edited the manuscript. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",
year = "2021",
month = jun,
day = "21",
doi = "10.1016/j.cub.2021.03.089",
language = "English (US)",
volume = "31",
pages = "2530--2538.e10",
journal = "Current Biology",
issn = "0960-9822",
publisher = "Cell Press",
number = "12",
}