Discovery of genomic intervals that underlie nematode responses to benzimidazoles.
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 cr...
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ftdoajarticles:oai:doaj.org/article:dff941417d364ba6bd42907fba8ecefa 2023-05-15T15:10:00+02:00 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 C Andersen 2018-03-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0006368 https://doaj.org/article/dff941417d364ba6bd42907fba8ecefa EN eng Public Library of Science (PLoS) http://europepmc.org/articles/PMC5895046?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0006368 https://doaj.org/article/dff941417d364ba6bd42907fba8ecefa PLoS Neglected Tropical Diseases, Vol 12, Iss 3, p e0006368 (2018) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2018 ftdoajarticles https://doi.org/10.1371/journal.pntd.0006368 2022-12-31T01:28:57Z 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. Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic PLOS Neglected Tropical Diseases 12 3 e0006368 |
institution |
Open Polar |
collection |
Directory of Open Access Journals: DOAJ Articles |
op_collection_id |
ftdoajarticles |
language |
English |
topic |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
spellingShingle |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Mostafa Zamanian Daniel E Cook Stefan Zdraljevic Shannon C Brady Daehan Lee Junho Lee Erik C Andersen Discovery of genomic intervals that underlie nematode responses to benzimidazoles. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
description |
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. |
format |
Article in Journal/Newspaper |
author |
Mostafa Zamanian Daniel E Cook Stefan Zdraljevic Shannon C Brady Daehan Lee Junho Lee Erik C Andersen |
author_facet |
Mostafa Zamanian Daniel E Cook Stefan Zdraljevic Shannon C Brady Daehan Lee Junho Lee Erik C Andersen |
author_sort |
Mostafa Zamanian |
title |
Discovery of genomic intervals that underlie nematode responses to benzimidazoles. |
title_short |
Discovery of genomic intervals that underlie nematode responses to benzimidazoles. |
title_full |
Discovery of genomic intervals that underlie nematode responses to benzimidazoles. |
title_fullStr |
Discovery of genomic intervals that underlie nematode responses to benzimidazoles. |
title_full_unstemmed |
Discovery of genomic intervals that underlie nematode responses to benzimidazoles. |
title_sort |
discovery of genomic intervals that underlie nematode responses to benzimidazoles. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2018 |
url |
https://doi.org/10.1371/journal.pntd.0006368 https://doaj.org/article/dff941417d364ba6bd42907fba8ecefa |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 12, Iss 3, p e0006368 (2018) |
op_relation |
http://europepmc.org/articles/PMC5895046?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0006368 https://doaj.org/article/dff941417d364ba6bd42907fba8ecefa |
op_doi |
https://doi.org/10.1371/journal.pntd.0006368 |
container_title |
PLOS Neglected Tropical Diseases |
container_volume |
12 |
container_issue |
3 |
container_start_page |
e0006368 |
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1766341079862345728 |