Natural Variation in a Chloride Channel Subunit Confers Avermectin Resistance in C. elegans

• Published in: Science (American Association for the Advancement of Science) Vol. 335; no. 6068; pp. 574 - 578
• Main Authors: Ghosh, Rajarshi, Andersen, Erik C., Shapiro, Joshua A., Gerke, Justin P., Kruglyak, Leonid
• Format: Journal Article
• Language: English
• Published: Washington, DC American Association for the Advancement of Science 03-02-2012; The American Association for the Advancement of Science
• Subjects: Alleles; Amino Acid Sequence; Amino acids; Animal tales; Animals; Animals, Genetically Modified; Antinematodal Agents - pharmacology; Bacteria; Biochemistry. Physiology. Immunology. Molecular biology; Biological and medical sciences; Caenorhabditis elegans - drug effects; Caenorhabditis elegans - genetics; Caenorhabditis elegans - physiology; Caenorhabditis elegans Proteins - chemistry; Caenorhabditis elegans Proteins - genetics; Caenorhabditis elegans Proteins - metabolism; Chemical control; Chloride channels; Chloride Channels - chemistry; Chloride Channels - genetics; Chloride Channels - metabolism; Control; Crosses, Genetic; Drug resistance; Drug Resistance - genetics; Fundamental and applied biological sciences. Psychology; Genes, Helminth; Genetic loci; Genetics of eukaryotes. Biological and molecular evolution; Genome-Wide Association Study; Haplotypes; Invertebrata; Invertebrates; Ivermectin - analogs & derivatives; Ivermectin - pharmacology; Ligands; Molecular Sequence Data; Mutation; Nemathelminthia. Plathelmintha; Nematodes; Parasitic diseases; Phenotypic traits; Physiology. Development; Phytopathology. Animal pests. Plant and forest protection; Polymorphism, Single Nucleotide; Population genetics, reproduction patterns; Protein Structure, Tertiary; Protozoa. Invertebrates; Quantitative Trait Loci; Selection, Genetic; Soil bacteria; Soil microorganisms; Streptomyces - physiology; Toxins; Worms; Nematicide; Genetic variability; Pesticides; Parasite; Ionic channel; Caenorhabditis elegans; Pest; Phytophagous; Sensitivity resistance; Chlorides; Helmintha; Nemathelminthia; Pesticide resistance; Invertebrata; Nematoda
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.1214318

Resistance of nematodes to anthelmintics such as avermectins has emerged as a major global health and agricultural problem, but genes conferring natural resistance to avermectins are unknown. We show that a naturally occurring four-amino-acid deletion in the ligand-binding domain of GLC-1, the alpha-subunit of a glutamate-gated chloride channel, confers resistance to avermectins in the model nematode Caenorhabditis elegans. We also find that the same variant confers resistance to the avermectin-producing bacterium Streptomyces avermitilis. Population-genetic analyses identified two highly divergent haplotypes at the glc-1 locus that have been maintained at intermediate frequencies by long-term balancing selection. These results implicate variation in glutamate-gated chloride channels in avermectin resistance and provide a mechanism by which such resistance can be maintained.