Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Animals
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Animals, Genetically Modified
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Antinematodal Agents / pharmacology*
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Caenorhabditis elegans / drug effects*
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Caenorhabditis elegans / genetics*
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Caenorhabditis elegans / physiology
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Caenorhabditis elegans Proteins / chemistry
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Caenorhabditis elegans Proteins / genetics*
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Caenorhabditis elegans Proteins / metabolism
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Chloride Channels / chemistry
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Chloride Channels / genetics*
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Chloride Channels / metabolism
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Crosses, Genetic
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Drug Resistance / genetics
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Genes, Helminth
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Genome-Wide Association Study
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Ivermectin / analogs & derivatives*
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Ivermectin / pharmacology*
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Ligands
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Molecular Sequence Data
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Mutation
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Polymorphism, Single Nucleotide
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Protein Structure, Tertiary
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Quantitative Trait Loci
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Selection, Genetic
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Streptomyces / physiology
Substances
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Antinematodal Agents
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Caenorhabditis elegans Proteins
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Chloride Channels
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Ligands
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glutamate-gated chloride channel 1, C elegans
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glutamate-gated chloride channels
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abamectin
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Ivermectin
Associated data
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GENBANK/JN983734
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GENBANK/JN983793