Natural variation in a chloride channel subunit confers avermectin resistance in C. elegans

Science. 2012 Feb 3;335(6068):574-8. doi: 10.1126/science.1214318.

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

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Animals, Genetically Modified
  • Antinematodal Agents / pharmacology*
  • Caenorhabditis elegans / drug effects*
  • Caenorhabditis elegans / genetics*
  • Caenorhabditis elegans / physiology
  • Caenorhabditis elegans Proteins / chemistry
  • Caenorhabditis elegans Proteins / genetics*
  • Caenorhabditis elegans Proteins / metabolism
  • Chloride Channels / chemistry
  • Chloride Channels / genetics*
  • Chloride Channels / metabolism
  • Crosses, Genetic
  • Drug Resistance / genetics
  • Genes, Helminth
  • Genome-Wide Association Study
  • Ivermectin / analogs & derivatives*
  • Ivermectin / pharmacology*
  • Ligands
  • Molecular Sequence Data
  • Mutation
  • Polymorphism, Single Nucleotide
  • Protein Structure, Tertiary
  • Quantitative Trait Loci
  • Selection, Genetic
  • Streptomyces / physiology

Substances

  • Antinematodal Agents
  • Caenorhabditis elegans Proteins
  • Chloride Channels
  • Ligands
  • glutamate-gated chloride channel 1, C elegans
  • glutamate-gated chloride channels
  • abamectin
  • Ivermectin

Associated data

  • GENBANK/JN983734
  • GENBANK/JN983793