Population genomics of anthelmintic resistance in parasitic nematodes of livestock : Haemonchus contortus as a model system

对害虫和病原体产生抗药性是21世纪的主要挑战之一。寄生线虫是后生动物寄生虫，对全球和加拿大畜牧业具有巨大的经济意义，其中耐药性是一个主要问题。我的研究计划的长期目标是全面了解家畜寄生虫是如何对药物(驱虫药)产生抗药性的，并将这一知识应用于改善监测和可持续控制。在这个发现资助项目中，我将应用种群基因组方法来研究驱虫药耐药性的遗传基础，以及导致其出现和传播的进化过程，使用小型反刍动物寄生虫缠绕血吸虫。这是一个很好的研究模型，因为这种寄生虫对主要驱虫药类别具有广泛的抗药性，拥有高质量的参考基因组，拥有优秀的种群遗传工具，是最容易实验驯化的动物寄生线虫之一。这也是加拿大养羊业面临的一个重要的新兴疾病问题。这次NSERC发现奖助金续签直接建立在我之前的工作基础上，并有以下具体目标。目的1调查驱虫药耐药性的来源和传播。深度测序方法将被用来提供对主要广谱驱虫药的已知和候选耐药基因座的耐药和敏感单倍型多样性的前所未有的看法。其目的是提供世界不同地区独立抗药性起源数量的第一张清晰图片，并测试主要候选抗病基因座以寻找选择的证据，从而在该领域具有相关性。目标2将进行全基因组扫描，以调查螺旋藻田间种群的选择特征。其目的是识别新的耐药基因座(以及证实或驳斥先前涉及的候选基因座的重要性)。这是一个重要的目标，因为有充分的证据表明，许多重要的驱虫抗药性基因座仍有待发现。目标3将研究物种间杂交是否导致缠绕线虫和近缘黄牛寄生虫Placei血吸虫之间的抗药性基因座的导入。其目的是提供一种概念证明，即抗药性可以在田间不同寄生线虫物种之间转移。这一目标还将提供另一种新的方法来识别新的耐药基因座(基于“超侵袭性”导入基因座的识别)。这一研究计划将提供一个极好的机会，将最先进的种群基因组方法应用于一个对全球粮食生产具有重大意义的重要实际问题。

The emergence of drug resistance to pests and pathogens is one of the major challenges of the 21st century. Parasitic nematodes are metazoan parasites that are of huge economic importance to the global and Canadian livestock industries and in which drug resistance is a major problem. Thelong term objective of my research program is to develop a comprehensive understanding of how livestock parasites become resistant to drugs (anthelmintics) and to apply this knowledge to improve surveillance and sustainable control. In this discovery grant project, I will apply population genomic approaches to investigate the genetic basis of anthelmintic drug resistance and the evolutionary processes leading to its emergence and spread using the small ruminant parasite Haemonchus contortus. This is an excellent study model since this parasite has widespread resistance to the major anthelmintic drug classes, has a high quality reference genome, has excellent population genetic tools and is one of the most experimentally tractable animal parasitic nematodes. It is also an important emerging disease problem for the Canadian sheep industry. This NSERC Discovery Grant renewal directly builds on my previous work and has the following specific objectives. Objective 1 will investigate the origin and spread of anthelmintic resistance. Deep sequencing approaches will be used to provide an unprecedented view of resistant and susceptible haplotype diversity at known, and candidate, drug resistance loci for the major broad spectrum anthelmintic drugs. The aim is to provide the first clear picture of the number of independent origins of resistance in different parts of the world and also to test the leading candidate resistance loci for evidence of selection and therefore relevance in the field. Objective 2 will undertake genome-wide scans to investigate signatures of selection in H. contortus field populations. The aim is to identify novel  drug resistance loci (as well as confirm or refute the importance of previously implicated candidate loci). This is an important aim since there is ample evidence that many important anthelmintic resistance loci remain to be discovered. Objective 3 will investigate whether interspecies hybridization leads to introgression of drug resistance loci between H. contortus and the closely related cattle parasite Haemonchus placei. The aim is to provide a proof-of-concept that drug resistance can be transferred between different parasitic nematode species in the field. This objective will also provide an additional novel approach to identify new drug resistance loci (based on the identification of "super invasive" introgressed loci). This program of research will provide an excellent opportunity to apply state-of-the-art population genomic approaches to an important practical problem that is of major significance to global food production.**