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PLoS Negl Trop Dis. 2018 Mar 30;12(3):e0006368. doi: 10.1371/journal.pntd.0006368. eCollection 2018 Mar.

Discovery of genomic intervals that underlie nematode responses to benzimidazoles.

Author information

1
Department of Pathobiological Sciences, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
2
Department of Molecular Biosciences, Northwestern University, Evanston, Illinois, United States of America.
3
Interdisciplinary Biological Science Program, Northwestern University, Evanston, Illinois, United States of America.
4
Institute of Molecular Biology and Genetics, Department of Biological Sciences, Seoul National University, Seoul, Korea.
5
Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois, United States of America.
6
Northwestern Institute on Complex Systems, Northwestern University, Evanston, Illinois, United States of America.

Abstract

Parasitic nematodes impose a debilitating health and economic burden across much of the world. Nematode resistance to anthelmintic drugs threatens parasite control efforts in both human and veterinary medicine. Despite this threat, the genetic landscape of potential resistance mechanisms to these critical drugs remains largely unexplored. Here, we exploit natural variation in the model nematodes Caenorhabditis elegans and Caenorhabditis briggsae to discover quantitative trait loci (QTL) that control sensitivity to benzimidazoles widely used in human and animal medicine. High-throughput phenotyping of albendazole, fenbendazole, mebendazole, and thiabendazole responses in panels of recombinant lines led to the discovery of over 15 QTL in C. elegans and four QTL in C. briggsae associated with divergent responses to these anthelmintics. Many of these QTL are conserved across benzimidazole derivatives, but others show drug and dose specificity. We used near-isogenic lines to recapitulate and narrow the C. elegans albendazole QTL of largest effect and identified candidate variants correlated with the resistance phenotype. These QTL do not overlap with known benzimidazole target resistance genes from parasitic nematodes and present specific new leads for the discovery of novel mechanisms of nematode benzimidazole resistance. Analyses of orthologous genes reveal conservation of candidate benzimidazole resistance genes in medically important parasitic nematodes. These data provide a basis for extending these approaches to other anthelmintic drug classes and a pathway towards validating new markers for anthelmintic resistance that can be deployed to improve parasite disease control.

PMID:
29601575
PMCID:
PMC5895046
DOI:
10.1371/journal.pntd.0006368
[Indexed for MEDLINE]
Free PMC Article

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