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Discovery of unique loci that underlie nematode responses to benzimidazoles

View ORCID ProfileMostafa Zamanian, Daniel E. Cook, View ORCID ProfileStefan Zdraljevic, Shannon C. Brady, Daehan Lee, Junho Lee, View ORCID ProfileErik Andersen
doi: https://doi.org/10.1101/116970
Mostafa Zamanian
University of Wisconsin-Madison;
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Daniel E. Cook
Northwestern University;
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Stefan Zdraljevic
Northwestern University;
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Shannon C. Brady
Northwestern University;
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Daehan Lee
Seoul National University
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Junho Lee
Seoul National University
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Erik Andersen
Northwestern University;
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  • For correspondence: erik.andersen@northwestern.edu
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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 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 significant 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.

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Posted October 31, 2017.
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Discovery of unique loci that underlie nematode responses to benzimidazoles
Mostafa Zamanian, Daniel E. Cook, Stefan Zdraljevic, Shannon C. Brady, Daehan Lee, Junho Lee, Erik Andersen
bioRxiv 116970; doi: https://doi.org/10.1101/116970
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Discovery of unique loci that underlie nematode responses to benzimidazoles
Mostafa Zamanian, Daniel E. Cook, Stefan Zdraljevic, Shannon C. Brady, Daehan Lee, Junho Lee, Erik Andersen
bioRxiv 116970; doi: https://doi.org/10.1101/116970

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