title: A dyf-7 haplotype causes sensory neuron defects and is associated with macrocyclic lactone resistance worldwide in the nematode parasite Haemonchus contortus.
abstract: Heavy reliance on macrocyclic lactones to treat parasitic nematodes has resulted in the evolution of widespread drug resistance that threatens human and animal health. Management strategies have been proposed that would slow the rise of resistance, however testing these strategies has been hampered by the lack of identified strong-effect resistance markers in parasites. We show that the Caenorhabditis elegans gene Cel_dyf-7, necessary for amphid sensory neuron development, also confers macrocyclic lactone sensitivity. In the sheep parasite Haemonchus contortus: (i) strains selected for macrocyclic lactone resistance were enriched in a Hco_dyf-7 haplotype that was rare in the drug-naïve population, (ii) the resistant haplotype correlated with the sensory neuron defects, and (iii) the resistant haplotype was associated with decreased Hco_dyf-7 expression. Resistant field isolates of H. contortus from five continents were enriched for the resistant haplotype, demonstrating the relevance of the Hco_dyf-7 haplotype to practise and indicating that it is a locus of strong effect. Hemizygosity resulting from sex linkage of dyf-7 likely contributes to the rise of resistance in treated populations.
authors.affiliation: Institute of Parasitology, 21111 Lakeshore, McGill University, Ste-Anne de Bellevue H9X3V9, Canada.
authors.forename: Ludmel
authors.initials: L
authors.lastname: Urdaneta-Marquez
authors.affiliation: Department of Biology, 1205 Ave. Docteur Penfield, McGill University, Montreal H3A1B1, Canada.
authors.forename: Seong Han
authors.initials: SH
authors.lastname: Bae
authors.affiliation: Department of Biology, 1205 Ave. Docteur Penfield, McGill University, Montreal H3A1B1, Canada.
authors.forename: Patrick
authors.initials: P
authors.lastname: Janukavicius
authors.affiliation: Institute of Parasitology, 21111 Lakeshore, McGill University, Ste-Anne de Bellevue H9X3V9, Canada.
authors.forename: Robin
authors.initials: R
authors.lastname: Beech
authors.affiliation: Department of Biology, 1205 Ave. Docteur Penfield, McGill University, Montreal H3A1B1, Canada.
authors.forename: Joseph
authors.initials: J
authors.lastname: Dent
authors.affiliation: Institute of Parasitology, 21111 Lakeshore, McGill University, Ste-Anne de Bellevue H9X3V9, Canada. Electronic address: roger.prichard@mcgill.ca.
authors.forename: Roger
authors.initials: R
authors.lastname: Prichard
mesh_terms: D000818:Animals; D000871:Anthelmintics / Q000494:pharmacology* / Q000627:therapeutic use; D029742:Caenorhabditis elegans Proteins / Q000235:genetics; D016009:Chi-Square Distribution; D018509:DNA, Helminth / Q000737:chemistry / Q000235:genetics; D004351:Drug Resistance; D005260:Female; D006188:Haemonchiasis / Q000188:drug therapy / Q000235:genetics / Q000469:parasitology / Q000662:veterinary*; D006189:Haemonchus / Q000235:genetics / Q000502:physiology*; D006239:Haplotypes; D006801:Humans; D007559:Ivermectin / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D008957:Models, Genetic; D030781:Organisms, Genetically Modified; D016133:Polymerase Chain Reaction; D011984:Sensory Receptor Cells / Q000502:physiology; D012756:Sheep; D012757:Sheep Diseases / Q000188:drug therapy / Q000235:genetics / Q000469:parasitology*
chemical_list: D000871:Anthelmintics; D029742:Caenorhabditis elegans Proteins; D018509:DNA, Helminth; D007559:Ivermectin
keywords: Amphids; Caenorhabditis elegans; Dyf-7; Haemonchus contortus; Ivermectin; Macrocyclic-lactone; Nematodes; Resistance