Genomic introgression mapping of field-derived multiple-anthelmintic resistance in Teladorsagia circumcincta

• Published in: PLoS genetics Vol. 13; no. 6; p. e1006857
• Main Authors: Choi, Young-Jun, Bisset, Stewart A, Doyle, Stephen R, Hallsworth-Pepin, Kymberlie, Martin, John, Grant, Warwick N, Mitreva, Makedonka
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 23-06-2017; Public Library of Science (PLoS)
• Subjects: Animals; Anthelmintic agents; Anthelmintics; Anthelmintics - therapeutic use; Bioinformatics; Biology and Life Sciences; Chemotherapy; Chromosome Mapping; Copy number; DNA Copy Number Variations - genetics; Dosage and administration; Drug resistance; Drug Resistance - genetics; Gene expression; Gene mapping; Gene polymorphism; Genes; Genetic aspects; Genomes; Genomics; Genotype; Grants; Health aspects; Humans; Inbreeding; Livestock; Medicine; Microbial drug resistance; Multidrug resistance; Parasites; Population; Regulatory sequences; Research and Analysis Methods; Roundworms; Sheep - parasitology; Soil sciences; Studies; Trichostrongyloidea - drug effects; Trichostrongyloidea - genetics; Trichostrongyloidea - pathogenicity; Trichostrongyloidiasis - drug therapy; Trichostrongyloidiasis - genetics; Trichostrongyloidiasis - parasitology; United States > US; Missouri
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1006857

Preventive chemotherapy has long been practiced against nematode parasites of livestock, leading to widespread drug resistance, and is increasingly being adopted for eradication of human parasitic nematodes even though it is similarly likely to lead to drug resistance. Given that the genetic architecture of resistance is poorly understood for any nematode, we have analyzed multidrug resistant Teladorsagia circumcincta, a major parasite of sheep, as a model for analysis of resistance selection. We introgressed a field-derived multiresistant genotype into a partially inbred susceptible genetic background (through repeated backcrossing and drug selection) and performed genome-wide scans in the backcross progeny and drug-selected F2 populations to identify the major genes responsible for the multidrug resistance. We identified variation linking candidate resistance genes to each drug class. Putative mechanisms included target site polymorphism, changes in likely regulatory regions and copy number variation in efflux transporters. This work elucidates the genetic architecture of multiple anthelmintic resistance in a parasitic nematode for the first time and establishes a framework for future studies of anthelmintic resistance in nematode parasites of humans.