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

Doyle, S. R. et al. (2019) Population genomic and evolutionary modelling analyses reveal a single major QTL for ivermectin drug resistance in the pathogenic nematode, Haemonchus contortus. BMC Genomics, 20, p. 218. (doi: 10.1186/s12864-019-5592-6) (PMID:30876405) (PMCID:PMC6420744)

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Abstract

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.

Item Type:Articles
Additional Information:Also funded by Wellcome Trust grants 098051 and 206194 and by a Sir Henry Dale Fellowship, jointly funded by Wellcome and the Royal Society (grant 101239/Z/13/Z).
Keywords:Population genetics, drug resistance, genetic mapping, Haemonchus contortus, genome sequencing, ivermectin.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Devaney, Professor Eileen and Laing, Dr Roz
Authors: Doyle, S. R., Illingworth, C. J.R., Laing, R., Bartley, D. J., Redman, E., Martinelli, A., Holroyd, N., Morrison, A. A., Rezansoff, A., Tracey, A., Devaney, E., Berriman, M., Sargison, N., Cotton, J. A., and Gilleard, J. S.
College/School:College of Medical Veterinary and Life Sciences > Institute of Biodiversity Animal Health and Comparative Medicine
Journal Name:BMC Genomics
Publisher:Biomed Central
ISSN:1471-2164
ISSN (Online):1471-2164
Copyright Holders:Copyright © 2019 The Authors
First Published:First published in BMC Genomics 20:218
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
190824The BUG consortium Building Upon the Genome: using H. contortus genomic resources to develop novel interventions to control endemic GI parasitesEileen DevaneyBiotechnology and Biological Sciences Research Council (BBSRC)BB/M003949/1Institute of Biodiversity, Animal Health and Comparative Medicine
165089microRNAs and drug resistance in parasitic nematodesEileen DevaneyWellcome Trust (WELLCOTR)094751/Z/10/ZInstitute of Biodiversity, Animal Health and Comparative Medicine
190824The BUG consortium Building Upon the Genome: using H. contortus genomic resources to develop novel interventions to control endemic GI parasitesEileen DevaneyBiotechnology and Biological Sciences Research Council (BBSRC)BB/M003949/1Institute of Biodiversity, Animal Health and Comparative Medicine