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MBE Advance Access published online on February 6, 2008
Molecular Biology and Evolution, doi:10.1093/molbev/msn025
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© The Author 2008. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

Research Article

Toxin-Resistant Sodium Channels: Parallel Adaptive Evolution Across a Complete Gene Family

Manda Clair Jost{dagger}, David M. Hillis{dagger}, Ying Lu{dagger}, John W. Kyle§, Harry A. Fozzard§ and Harold H. Zakon{dagger}

{dagger} Sections of Integrative Biology and Neurobiology, and Center for Computational Biology, School of Biological Sciences, University of Texas at Austin, Patterson Laboratories C0930, 24th and Speedway, Austin TX 78712, USA
§ Department of Medicine, Division of Biological Sciences, University of Chicago, 5801 South Ellis, Chicago IL 60637, USA

Corresponding Author: M.C. Jost – use address above, Email: mandaclair{at}mail.utexas.edu, Mobile: (575) 921-9245, Lab: (512) 232-6283

Received for publication October 17, 2007. Revision received January 14, 2008. Revision received January 22, 2008. Approximately 75% of vertebrate proteins belong to protein families encoded by multiple evolutionarily-related genes, a pattern that emerged as a result of gene and genome duplications over the course of vertebrate evolution. In families of genes with similar or related functions, adaptation to a strong selective agent should involve multiple adaptive changes across the entire gene family. However, we know of no evolutionary studies that have explicitly addressed this point. Here we show how four taxonomically diverse species of pufferfishes (Tetraodontidae) each evolved resistance to the guanidinium toxins tetrodotoxin (TTX) and saxitoxin (STX) via parallel amino acid replacements across all eight sodium channels present in teleost fish genomes. This resulted in diverse suites of coexisting sodium channel types that all confer varying degrees of toxin resistance, yet show remarkable convergence among genes and phylogenetically diverse species. Using site-directed mutagenesis and expression of a vertebrate sodium channel, we also demonstrate that resistance to TTX/STX is enhanced up to 15-fold by single, frequently-observed replacements at two sites that have not previously been implicated in toxin binding, but show similar or identical replacements in pufferfishes and in distantly-related vertebrate and non-vertebrate animals. This study presents an example of natural selection acting upon a complete gene family, repeatedly arriving at a diverse but limited number of adaptive changes within the same genome. To be maximally informative, we suggest that future studies of molecular adaptation should consider all functionally similar paralogs of the affected gene family.

Key Words: adaptation • parallel evolution • gene families • sodium channels • tetrodotoxin • saxitoxin


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