Population genomics of ivermectin drug resistance in parasitic nematodes of livestock

对用于控制害虫和病原体的药物的耐药性是当今的主要全球挑战之一。家畜胃肠道线虫（GIN）寄生虫的驱虫药耐药性问题日益严重，对加拿大和世界其他地区的农业经济、动物福利和粮食安全构成重大威胁。我的总体研究计划的长期目标是全面了解线虫寄生虫如何对驱虫药产生耐药性，以改善诊断和可持续控制。伊维菌素是迄今为止最重要的家畜寄生虫控制药物，其对动物和人类健康的重要性被2015年诺贝尔医学或生理学奖所认可。伊维菌素耐药性在多种牲畜GIN物种中越来越普遍，尽管该药物在全球仍然具有重要性，但耐药性的遗传基础仍然是一个谜。大多数以前的伊维菌素耐药性研究集中在候选基因的研究，未能确定主要的遗传决定因素。这个NSERC发现提案将建立在我们以前的工作基础上，并利用群体基因组学和进化生物学的力量来阐明伊维菌素抗性的遗传基础。在这样做的时候，它也将解决有关在该领域的驱虫药耐药性的演变的基本问题。抗性的遗传决定因素在多大程度上是不同线虫物种和不同地理区域趋同进化的结果，将被探索和利用，以帮助确定因果抗性突变。该项目将调查伊维菌素耐药性的起源和模式，以及在加拿大和世界其他几个地区绵羊和牛的最重要的GIN寄生虫中的传播。该项目将首先侧重于捻转血矛线虫，这是一种小型反刍动物GIN寄生虫，具有驱虫药抗性研究的最佳可用工具，然后对密切相关的经济上重要的GIN牛种进行比较分析。我们将建立在我们的一个主要QTL在实验室选择的H。通过研究田间种群，目的1：应用群体基因组学技术研究伊维菌素耐药的主要遗传位点。contortus现场种群。目的2：研究伊维菌素耐药性的趋同进化程度，重点是最重要的GIN牛种属。目的3：调查绵羊和牛GIN寄生虫中伊维菌素耐药性出现和传播的全球模式。除了具有基本的科学意义外，确定耐药性的遗传决定因素对于开发急需的分子诊断测试是必要的。了解耐药性出现和传播的模式将为放牧和生物安全管理等缓解战略提供所需的证据基础。

Resistance to the drugs used to control pests and pathogens is one of today's major global challenges. Anthelmintic drug resistance in GastroIntestinal Nematode (GIN) parasites of livestock is increasingly problematic and a significant threat to agricultural economics, animal welfare and food security in Canada and the rest of the world. The long-term objective of my overall research program is to develop a comprehensive understanding of how nematode parasites become resistant to anthelmintic drugs to improve diagnosis and sustainable control. Ivermectin is the by far the most important drug for livestock parasite control with its importance to animal and human health being recognized by the 2015 Nobel Prize for Medicine or Physiology. Ivermectin resistance is increasingly widespread in multiple livestock GIN species and, in spite of the continued global importance of this drug, the genetic basis of resistance remains an enigma. Most previous ivermectin resistance research has focused on candidate gene studies which have failed to identify the major genetic determinants. This NSERC Discovery proposal will build on our previous work and use the power of population genomics and evolutionary biology to elucidate the genetic basis of ivermectin resistance. In doing so, it will also address fundamental questions regarding the evolution of anthelmintic resistance in the field. The extent to which the genetic determinants of resistance are the result of convergent evolution in different nematode species, and in different geographical regions, will be explored and exploited to help identify causal resistance mutations. The project will investigate the origins and patterns of ivermectin resistance emergence and spread in the most important GIN parasites of sheep and cattle in Canada and several other regions of the world. The project will first focus on Haemonchus contortus, a small ruminant GIN parasite which has the best available tools for anthelmintic resistance research, and then undertake comparative analysis of closely related, economically important, GIN species of cattle. We will build on our discovery of a major QTL in laboratory-selected H. contortus strains by studying field populations. Objective 1: Application of population genomics to identify the major genetic loci underlying ivermectin resistance in H. contortus field populations. Objective 2: Investigation of the extent of convergent evolution of ivermectin resistance focusing on the most important GIN species of cattle. Objective 3: Investigation of the global patterns of ivermectin resistance emergence and spread in GIN parasites of sheep and cattle. As well as being of fundamental scientific interest, identifying the genetic determinants of resistance is necessary to develop much needed molecular diagnostic tests. Understanding patterns of resistance emergence and spread will provide the required evidence-base for mitigation strategies such as grazing and biosecurity management.