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This poison is broadly employed as a potent antipredator defence, blocking voltage\u2010gated sodium channels (Na<jats:sub>v<\/jats:sub>) in muscles and nerves, paralysing and sometimes killing predators. Resistance in taxa bearing this neurotoxin and a few predators appears to come from convergent replacements in specific Na<jats:sub>v<\/jats:sub> residues that interact with TTX. This stereotyped genetic response suggests molecular and phenotypic evolution may be constrained and predictable. Here, we investigate the extent of mechanistic convergence in garter snakes (<jats:italic>Thamnophis<\/jats:italic>) that prey on TTX\u2010bearing newts (<jats:italic>Taricha<\/jats:italic>) by examining the physiological and genetic basis of TTX resistance in the Sierra garter snake (<jats:italic>Th.\u00a0couchii<\/jats:italic>). We characterize variation in this predatory adaptation across populations at several biological scales: whole\u2010animal TTX resistance; skeletal muscle resistance; functional genetic variation in three Na<jats:sub>v<\/jats:sub> encoding loci; and levels of gene expression for one of these loci. We found <jats:italic>Th.\u00a0couchii<\/jats:italic> possess extensive geographical variation in resistance at the whole\u2010animal and skeletal muscle levels. As in other <jats:italic>Thamnophis<\/jats:italic>, resistance at both levels is highly correlated, suggesting convergence across the biological levels linking organism to organ. However, <jats:italic>Th.\u00a0couchii<\/jats:italic> shows no functional variation in Na<jats:sub>v<\/jats:sub> loci among populations or difference in candidate gene expression. Local variation in TTX resistance in <jats:italic>Th.\u00a0couchii<\/jats:italic> cannot be explained by the same relationship between genotype and phenotype seen in other taxa. Thus, historical contingencies may lead different species of <jats:italic>Thamnophis<\/jats:italic> down alternative routes to local adaptation.<\/jats:p>","DOI":"10.1111\/mec.16538","type":"journal-article","created":{"date-parts":[[2022,5,21]],"date-time":"2022-05-21T14:34:55Z","timestamp":1653143695000},"page":"3827-3843","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["The road not taken: Evolution of tetrodotoxin resistance in the Sierra garter snake (<i>Thamnophis couchii<\/i>) by a path less travelled"],"prefix":"10.1111","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6536-7039","authenticated-orcid":false,"given":"Jessica S.","family":"Reimche","sequence":"first","affiliation":[{"name":"Department of Biology University of Nevada  Reno Nevada USA"},{"name":"Program in Ecology, Evolution, and Conservation Biology University of Nevada  Reno Nevada 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