title: Evolutionary history of a complex adaptation: tetrodotoxin resistance in salamanders.
abstract: Understanding the processes that generate novel adaptive phenotypes is central to evolutionary biology. We used comparative analyses to reveal the history of tetrodotoxin (TTX) resistance in TTX-bearing salamanders. Resistance to TTX is a critical component of the ability to use TTX defensively but the origin of the TTX-bearing phenotype is unclear. Skeletal muscle of TTX-bearing salamanders (modern newts, family: Salamandridae) is unaffected by TTX at doses far in excess of those that block action potentials in muscle and nerve of other vertebrates. Skeletal muscle of non-TTX-bearing salamandrids is also resistant to TTX but at lower levels. Skeletal muscle TTX resistance in the Salamandridae results from the expression of TTX-resistant variants of the voltage-gated sodium channel NaV 1.4 (SCN4a). We identified four substitutions in the coding region of salSCN4a that are likely responsible for the TTX resistance measured in TTX-bearing salamanders and variation at one of these sites likely explains variation in TTX resistance among other lineages. Our results suggest that exaptation has played a role in the evolution of the TTX-bearing phenotype and provide empirical evidence that complex physiological adaptations can arise through the accumulation of beneficial mutations in the coding region of conserved proteins.
authors.affiliation: Uintah Basin Campus, Utah State University, Vernal, Utah, 84078. charles.hanifin@usu.edu.
authors.forename: Charles T
authors.initials: CT
authors.lastname: Hanifin
authors.forename: William F
authors.initials: WF
authors.lastname: Gilly
mesh_terms: D000200:Action Potentials; D000222:Adaptation, Physiological; D000595:Amino Acid Sequence; D000818:Animals; D004351:Drug Resistance; D019143:Evolution, Molecular; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000187:drug effects / Q000502:physiology; D062553:NAV1.4 Voltage-Gated Sodium Channel / Q000235:genetics*; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D013779:Tetrodotoxin / Q000494:pharmacology*; D014562:Caudata / Q000235:genetics* / Q000502:physiology
chemical_list: D062553:NAV1.4 Voltage-Gated Sodium Channel; D026941:Sodium Channel Blockers; D013779:Tetrodotoxin
keywords: Adaptation; Caudata; Salamandridae; evolutionary genomics; molecular evolution