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抗药性是当今全球面临的主要挑战之一。家畜胃肠道线虫(GIN)寄生虫对驱虫药的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。我整个研究计划的长期目标是全面了解线虫寄生虫是如何对驱虫药产生抗药性的，以改进诊断和可持续控制。伊维菌素是迄今为止控制牲畜寄生虫最重要的药物，其对动物和人类健康的重要性得到了2015年诺贝尔医学或生理学奖的认可。伊维菌素耐药性在多种家畜杜松子酒品种中越来越普遍，尽管这种药物仍然具有全球重要性，但耐药性的遗传基础仍然是一个谜。以前的大多数伊维菌素耐药性研究都集中在候选基因研究上，未能确定主要的遗传决定因素。NSERC的这项发现计划将建立在我们之前工作的基础上，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耐药性的遗传基础。在这样做的同时，它还将解决有关田间驱虫剂抗药性演变的基本问题。将探索和利用抗药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，以帮助识别原因抗药性突变。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最重要的绵羊和牛的杜松子寄生虫中出现和传播的情况。该项目首先将重点放在缠绕血圆线虫上，这是一种小型反刍动物杜松子虫寄生虫，拥有研究驱虫药耐药性的最佳工具，然后对密切相关的、经济上重要的杜松子牛品种进行比较分析。我们将通过研究田间种群，在实验室选择的扭曲线虫菌株中发现一个主要的QTL。目的1：应用种群基因组学方法确定螺旋藻种群对伊维菌素抗性的主要遗传位点。目的：以牛中最重要的杜松子酒品种为研究对象，调查伊维菌素耐药性的趋同进化程度。目的：调查伊维菌素耐药性在绵羊和牛的肠道寄生虫中的出现和传播的全球模式。除了具有基本的科学意义外，识别抗药性的遗传决定因素对于开发急需的分子诊断测试也是必要的。了解抗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必要的证据基础。

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.