Evolutionary genetics of adaptation to toxins in animals

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Project Summary/Abstract An important goal in biology is to link genotype with phenotype for traits that affect fitness. The unique adaptations found in animals that sequester neurotoxins are a useful model for understanding the genetic underpinnings of simple and complex traits that are relevant to human medicine. Specifically, neurotoxins target ion channel proteins that are critical for nervous system function. In humans, mutations in single ion channel genes can cause diseases such as epilepsy, myotonia, cystic fibrosis, migraines, and diabetes. However, animals often resist neurotoxins through mutations in these same ion channels, usually without suffering from disease phenotypes. Understanding how diverse organisms fine tune the function of ion channels without causing disease provides important information regarding the genetics of ion channel function and disease. Animals that not only resist but also sequester toxins likely modulate multi-gene pathways underlying toxin metabolism and transport, ultimately leading to selective toxin accumulation into specific tissues at high concentrations. The few known genes involved in toxin sequestration also play critical roles in drug resistance (e.g., multi-drug transporters) and metabolism (cytochrome p450s) in humans. Thus, resistance and sequestration mechanisms parallel pharmaceutical goals to efficiently deliver drugs to specific targets and/or tissues while avoiding drug breakdown or insensitivity. The proposed research aims to further our understanding of the genetic basis of toxin resistance (simple) and sequestration (complex) mechanisms by leveraging state-of-the-art approaches in model and non- model systems. In amphibians, tetrodotoxin resistance has been traced to mutations in ion channels, and tetrodotoxin is thought to be sequestered from symbiotic bacteria. The proposed research will determine whether Harlequin toads obtain toxins from bacteria through bacterial culturing and inoculation experiments. Researchers will then use transcriptome sequencing to determine whether Harlequin toads and Pacific newts modulate production and storage of TTX through specific protein activity in skin tissue. In another project, researchers will identify genes and pathways involved in epibatidine sequestration using toxin-feeding experiments, RNA sequencing, and whole-genome sequencing in poison frogs that can and cannot sequester epibatidine. Finally, researchers will experimentally evolve nicotine sequestration in fruit flies to identify genes and pathways underlying toxin sequestration with unprecedented detail. Understanding the mechanisms used by animals to modulate toxin accumulation and clearance will provide insight into the suite of genes that interact with toxins as they are ingested, transported, stored, or excreted. Given that neurotoxins target critical nervous system proteins and interact with several biological pathways targeted by human medicine, the proposed research has translational implications for pharmacology and the biology of disease.