Natural variation in a chloride channel subunit confers avermectin resistance in C. elegans.
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.
Lewis-Sigler Institute for Integrative Genomics, Department of Ecology and Evolutionary Biology, and Howard Hughes Medical Institute, Princeton University, Princeton, NJ 08544, USA.
Rajarshi
R
Ghosh
Erik C
EC
Andersen
Joshua A
JA
Shapiro
Justin P
JP
Gerke
Leonid
L
Kruglyak
D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D000969:Antinematodal Agents / Q000494:pharmacology*; D017173:Caenorhabditis elegans / Q000187:drug effects* / Q000235:genetics* / Q000502:physiology; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D018118:Chloride Channels / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D003433:Crosses, Genetic; D004351:Drug Resistance / Q000235:genetics; D017238:Genes, Helminth; D055106:Genome-Wide Association Study; D007559:Ivermectin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D008024:Ligands; D008969:Molecular Sequence Data; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D017434:Protein Structure, Tertiary; D040641:Quantitative Trait Loci; D012641:Selection, Genetic; D013302:Streptomyces / Q000502:physiology
D000969:Antinematodal Agents; D029742:Caenorhabditis elegans Proteins; D018118:Chloride Channels; D008024:Ligands; C570054:glutamate-gated chloride channel 1, C elegans; C109777:glutamate-gated chloride channels; C048324:abamectin; D007559:Ivermectin