Discovery of genomic intervals that underlie nematode responses to benzimidazoles

Mostafa Zamanian*, Daniel E. Cook, Stefan Zdraljevic, Shannon C. Brady, Daehan Lee, Junho Lee, Erik Christian Andersen

*Corresponding author for this work

Research output: Contribution to journalArticle

6 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere0006368
JournalPLoS Neglected Tropical Diseases
Volume12
Issue number3
DOIs
StatePublished - Mar 30 2018

Fingerprint

Benzimidazoles
Quantitative Trait Loci
Anthelmintics
Caenorhabditis elegans
Communicable Disease Control
Albendazole
Pharmaceutical Preparations
Caenorhabditis
Fenbendazole
Thiabendazole
Mebendazole
Genes
Veterinary Medicine
Internal-External Control
Economics
Medicine
Phenotype
benzimidazole
Health

ASJC Scopus subject areas

  • Public Health, Environmental and Occupational Health
  • Infectious Diseases

Cite this

Zamanian, Mostafa ; Cook, Daniel E. ; Zdraljevic, Stefan ; Brady, Shannon C. ; Lee, Daehan ; Lee, Junho ; Andersen, Erik Christian. / Discovery of genomic intervals that underlie nematode responses to benzimidazoles. In: PLoS Neglected Tropical Diseases. 2018 ; Vol. 12, No. 3.
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Discovery of genomic intervals that underlie nematode responses to benzimidazoles. / Zamanian, Mostafa; Cook, Daniel E.; Zdraljevic, Stefan; Brady, Shannon C.; Lee, Daehan; Lee, Junho; Andersen, Erik Christian.

In: PLoS Neglected Tropical Diseases, Vol. 12, No. 3, e0006368, 30.03.2018.

Research output: Contribution to journalArticle

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T1 - Discovery of genomic intervals that underlie nematode responses to benzimidazoles

AU - Zamanian, Mostafa

AU - Cook, Daniel E.

AU - Zdraljevic, Stefan

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AU - Lee, Daehan

AU - Lee, Junho

AU - Andersen, Erik Christian

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