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Population genomic and evolutionary modelling analyses reveal a single major QTL for ivermectin drug resistance in the pathogenic nematode, Haemonchus contortus

BACKGROUND: Infections with helminths cause an enormous disease burden in billions of animals and plants worldwide. Large scale use of anthelmintics has driven the evolution of resistance in a number of species that infect livestock and companion animals, and there are growing concerns regarding the...

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Autores principales: Doyle, Stephen R., Illingworth, Christopher J. R., Laing, Roz, Bartley, David J., Redman, Elizabeth, Martinelli, Axel, Holroyd, Nancy, Morrison, Alison A., Rezansoff, Andrew, Tracey, Alan, Devaney, Eileen, Berriman, Matthew, Sargison, Neil, Cotton, James A., Gilleard, John S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6420744/
https://www.ncbi.nlm.nih.gov/pubmed/30876405
http://dx.doi.org/10.1186/s12864-019-5592-6
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author Doyle, Stephen R.
Illingworth, Christopher J. R.
Laing, Roz
Bartley, David J.
Redman, Elizabeth
Martinelli, Axel
Holroyd, Nancy
Morrison, Alison A.
Rezansoff, Andrew
Tracey, Alan
Devaney, Eileen
Berriman, Matthew
Sargison, Neil
Cotton, James A.
Gilleard, John S.
author_facet Doyle, Stephen R.
Illingworth, Christopher J. R.
Laing, Roz
Bartley, David J.
Redman, Elizabeth
Martinelli, Axel
Holroyd, Nancy
Morrison, Alison A.
Rezansoff, Andrew
Tracey, Alan
Devaney, Eileen
Berriman, Matthew
Sargison, Neil
Cotton, James A.
Gilleard, John S.
author_sort Doyle, Stephen R.
collection PubMed
description BACKGROUND: Infections with helminths cause an enormous disease burden in billions of animals and plants worldwide. Large scale use of anthelmintics has driven the evolution of resistance in a number of species that infect livestock and companion animals, and there are growing concerns regarding the reduced efficacy in some human-infective helminths. Understanding the mechanisms by which resistance evolves is the focus of increasing interest; robust genetic analysis of helminths is challenging, and although many candidate genes have been proposed, the genetic basis of resistance remains poorly resolved. RESULTS: Here, we present a genome-wide analysis of two genetic crosses between ivermectin resistant and sensitive isolates of the parasitic nematode Haemonchus contortus, an economically important gastrointestinal parasite of small ruminants and a model for anthelmintic research. Whole genome sequencing of parental populations, and key stages throughout the crosses, identified extensive genomic diversity that differentiates populations, but after backcrossing and selection, a single genomic quantitative trait locus (QTL) localised on chromosome V was revealed to be associated with ivermectin resistance. This QTL was common between the two geographically and genetically divergent resistant populations and did not include any leading candidate genes, suggestive of a previously uncharacterised mechanism and/or driver of resistance. Despite limited resolution due to low recombination in this region, population genetic analyses and novel evolutionary models supported strong selection at this QTL, driven by at least partial dominance of the resistant allele, and that large resistance-associated haplotype blocks were enriched in response to selection. CONCLUSIONS: We have described the genetic architecture and mode of ivermectin selection, revealing a major genomic locus associated with ivermectin resistance, the most conclusive evidence to date in any parasitic nematode. This study highlights a novel genome-wide approach to the analysis of a genetic cross in non-model organisms with extreme genetic diversity, and the importance of a high-quality reference genome in interpreting the signals of selection so identified. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12864-019-5592-6) contains supplementary material, which is available to authorized users.
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spelling pubmed-64207442019-03-28 Population genomic and evolutionary modelling analyses reveal a single major QTL for ivermectin drug resistance in the pathogenic nematode, Haemonchus contortus Doyle, Stephen R. Illingworth, Christopher J. R. Laing, Roz Bartley, David J. Redman, Elizabeth Martinelli, Axel Holroyd, Nancy Morrison, Alison A. Rezansoff, Andrew Tracey, Alan Devaney, Eileen Berriman, Matthew Sargison, Neil Cotton, James A. Gilleard, John S. BMC Genomics Research Article BACKGROUND: Infections with helminths cause an enormous disease burden in billions of animals and plants worldwide. Large scale use of anthelmintics has driven the evolution of resistance in a number of species that infect livestock and companion animals, and there are growing concerns regarding the reduced efficacy in some human-infective helminths. Understanding the mechanisms by which resistance evolves is the focus of increasing interest; robust genetic analysis of helminths is challenging, and although many candidate genes have been proposed, the genetic basis of resistance remains poorly resolved. RESULTS: Here, we present a genome-wide analysis of two genetic crosses between ivermectin resistant and sensitive isolates of the parasitic nematode Haemonchus contortus, an economically important gastrointestinal parasite of small ruminants and a model for anthelmintic research. Whole genome sequencing of parental populations, and key stages throughout the crosses, identified extensive genomic diversity that differentiates populations, but after backcrossing and selection, a single genomic quantitative trait locus (QTL) localised on chromosome V was revealed to be associated with ivermectin resistance. This QTL was common between the two geographically and genetically divergent resistant populations and did not include any leading candidate genes, suggestive of a previously uncharacterised mechanism and/or driver of resistance. Despite limited resolution due to low recombination in this region, population genetic analyses and novel evolutionary models supported strong selection at this QTL, driven by at least partial dominance of the resistant allele, and that large resistance-associated haplotype blocks were enriched in response to selection. CONCLUSIONS: We have described the genetic architecture and mode of ivermectin selection, revealing a major genomic locus associated with ivermectin resistance, the most conclusive evidence to date in any parasitic nematode. This study highlights a novel genome-wide approach to the analysis of a genetic cross in non-model organisms with extreme genetic diversity, and the importance of a high-quality reference genome in interpreting the signals of selection so identified. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12864-019-5592-6) contains supplementary material, which is available to authorized users. BioMed Central 2019-03-15 /pmc/articles/PMC6420744/ /pubmed/30876405 http://dx.doi.org/10.1186/s12864-019-5592-6 Text en © The Author(s). 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Doyle, Stephen R.
Illingworth, Christopher J. R.
Laing, Roz
Bartley, David J.
Redman, Elizabeth
Martinelli, Axel
Holroyd, Nancy
Morrison, Alison A.
Rezansoff, Andrew
Tracey, Alan
Devaney, Eileen
Berriman, Matthew
Sargison, Neil
Cotton, James A.
Gilleard, John S.
Population genomic and evolutionary modelling analyses reveal a single major QTL for ivermectin drug resistance in the pathogenic nematode, Haemonchus contortus
title Population genomic and evolutionary modelling analyses reveal a single major QTL for ivermectin drug resistance in the pathogenic nematode, Haemonchus contortus
title_full Population genomic and evolutionary modelling analyses reveal a single major QTL for ivermectin drug resistance in the pathogenic nematode, Haemonchus contortus
title_fullStr Population genomic and evolutionary modelling analyses reveal a single major QTL for ivermectin drug resistance in the pathogenic nematode, Haemonchus contortus
title_full_unstemmed Population genomic and evolutionary modelling analyses reveal a single major QTL for ivermectin drug resistance in the pathogenic nematode, Haemonchus contortus
title_short Population genomic and evolutionary modelling analyses reveal a single major QTL for ivermectin drug resistance in the pathogenic nematode, Haemonchus contortus
title_sort population genomic and evolutionary modelling analyses reveal a single major qtl for ivermectin drug resistance in the pathogenic nematode, haemonchus contortus
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6420744/
https://www.ncbi.nlm.nih.gov/pubmed/30876405
http://dx.doi.org/10.1186/s12864-019-5592-6
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