Abstract
Like other pathogens, parasitic helminths can rapidly evolve resistance to drug treatment. Understanding the genetic basis of anthelmintic drug resistance in parasitic nematodes is key to tracking its spread and improving the efficacy and sustainability of parasite control. Here, we use an
in vivo
genetic cross between drug-susceptible and multi-drug-resistant strains of
Haemonchus contortus
in a natural host-parasite system to simultaneously map resistance loci for the three major classes of anthelmintics. This approach identifies new alleles for resistance to benzimidazoles and levamisole and implicates the transcription factor
cky-1
in ivermectin resistance. This gene is within a locus under selection in ivermectin-resistant populations worldwide; expression analyses and functional validation using knockdown experiments support that
cky-1
is associated with ivermectin survival. Our work demonstrates the feasibility of high-resolution forward genetics in a parasitic nematode and identifies variants for the development of molecular diagnostics to combat drug resistance in the field.
•
High genomic diversity differentiates susceptible and multi-drug-resistant helminths
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A forward genetic cross reveals QTLs that are specific to each of three drug classes
•
Novel causal variants are defined for benzimidazole and levamisole anthelmintics
•
cky-1
expression is correlated with ivermectin resistance in three nematode species
Doyle et al. describe a forward genetic cross between susceptible and multi-drug-resistant strains of the globally distributed parasitic worm
Haemonchus contortus
. Whole-genome analysis reveals loci associated with resistance to each drug class, and novel resistance alleles are validated for two classes.