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. Author summary Teladorsagia circumcincta is an economically significant nematode (roundworm) pathogen affecting sheep and goats in temperate regions of the world. The widespread use of prophylactic treatment has resulted in rapid selection for anthelmintic (anti-worm drug) resistance in this and other species of livestock parasites. The mechanism of resistance is not well understood because most studies have focused on the role of candidate genes using simplistic models of single gene selection, despite evidence that the evolution of resistance is more complex. Here, we report on a comprehensive whole-genome analysis that elucidated resistance-associated genes, which was facilitated by developing a pair of T . circumcincta strains sharing a largely common genetic background but differing markedly in their susceptibility to anthelmintic drugs. The results show that multiple genetic factors contribute to anthelmintic resistance in a variety of ways, including possible reduction/modulation in target site sensitivity, reduced target site expression, and increased drug efflux, to name a few. This suggests that drug resistance in these parasites is a multifactorial quantitative trait rather than a simple discrete Mendelian character. With this study, we established a genomics-based experimental paradigm for investigating anthelmintic resistance, at a time when its medical importance is rapidly increasing.
【초록키워드】 Evolution, susceptibility, Variation, Genetic, polymorphism, drugs, parasites, Population, Chemotherapy, sensitivity, Region, pathogen, humans, Genotype, eradication, drug resistance, livestock, sheep, expression, Quantitative, mechanism, Evidence, Analysis, strain, candidate gene, framework, Multidrug resistance, lead, genetic factors, copy number, Factor, complex, pair, genetic background, resistance gene, genetic architecture, parasite, parasitic nematodes, prophylactic treatment, Putative mechanisms, regulatory region, progeny, single gene, multifactorial, whole-genome, Genes, repeated, widespread, susceptible, multidrug resistant, responsible, analyzed, identify, performed, reduced, facilitated, changes in, contribute, variety, adopted, affecting, increasingly, parasitic nematode,