The generation and maintenance of genetic novelty in helminth populations

蠕虫，通常被称为寄生蠕虫，是一群生物，它们利用各种各样的宿主和生活史策略来实现世代相传。人类和对兽医有重要意义的动物（如伴侣动物和食用动物）的寄生虫感染会给其宿主造成严重的疾病负担，在世界各地造成疼痛、残疾、发育迟缓，在某些情况下甚至导致死亡。在世界范围内，任何时候都有超过15亿人和无数动物感染一种或多种寄生虫。因此，人类寄生虫感染是大规模大规模药物管理运动的目标，在兽医环境中，数亿只动物接受驱虫药治疗，以预防和/或治愈感染。驱虫药对治疗蠕虫感染的重要性不容低估；伊维菌素作为一种驱虫剂的发现和发展获得了2015年诺贝尔生理学或医学奖的认可。蠕虫在宿主体内或宿主外生存和适应的能力取决于它们产生和保持重要的遗传新颖性的能力，而选择可以根据这种新颖性起作用，这反过来又决定了它们的适应潜力。两个例子清楚地说明了这种适应潜力：(i)寄生虫寄生于单一或多个宿主物种的能力在其进化史上多次从独立生活的祖先中产生，不同种类的寄生虫利用不同的机制入侵和建立宿主；（ii）广泛和频繁地使用驱虫药来控制寄生虫，迅速选择了耐药寄生虫。只有三种广谱驱虫剂可用；在兽医动物（特别是牲畜）中，在引进该药物后短短几年内，世界各地许多蠕虫物种都对所有类别（包括同时对多个类别）产生了耐药性。在人类中，人们越来越担心这些相同药物的疗效下降是出现耐药性的证据，这有可能使长达30年的成功治疗和寄生虫控制所取得的成果付之一篑。然而，人们对这种适应的遗传基础知之甚少。我们知识上的这一重大差距，主要是由于大多数蠕虫物种的高度遗传多样性和实验上的难处，限制了我们理解这些过程的能力，而要成功治疗疾病和预测长期控制规划的结果，就需要克服这些过程。我的工作是确定寄生虫适应的遗传机制。为此，我将首先关注使用伊维菌素（一种对人类和动物健康至关重要的药物）进行药物选择对扭曲血蜱（Haemonchus tortus）遗传多样性的影响。扭曲血蜱是全球牲畜的一种主要经济上重要的胃肠道寄生虫，也是一种用于药物发现、疫苗开发和抗虫性研究的遗传易处理模型。利用易感菌株和耐伊维菌素菌株之间的遗传杂交来控制遗传多样性，结合高通量群体和单细胞基因组方法在多年进化实验中取样遗传多样性，本研究将剖析遗传和表型变异之间的相互作用，以及选择对形成这种变异的影响。此外，这些数据将显示它们未来适应的潜力，并确定可能用于新型控制干预措施的进化限制。从更广泛的意义上说，这些数据将为改善暴露于像弓形螺旋体这样的寄生虫的动物的健康和福利的实践提供信息，并为理解具有人类和兽医医学重要性的遗传顽固性蠕虫物种的适应潜力提供新的实验和理论框架

Helminths, commonly called parasitic worms, are a group of organisms that exploit an incredibly diverse range of hosts and life history strategies for their persistence across generations. Helminth infections of humans and animals of veterinary importance, such as companion and food-producing animals, are responsible for a significant disease burden in their hosts that causes pain, disability, developmental delay, and in some cases, death around the world. Worldwide, over 1.5 billion people and countless animals are infected with one or more helminth species at any given time. As such, human helminth infections are the target of large-scale mass drug administration campaigns, and in veterinary settings, hundreds of millions of animals are treated with anthelmintic drugs to prevent and/or cure infections. The importance of anthelmintics to treat helminth infections cannot be understated; the discovery and development of ivermectin as an anthelmintic was recognised by a Nobel Prize in Physiology or Medicine in 2015.The ability of helminths to survive and adapt within or outside their hosts lies in their capacity to generate and maintain significant genetic novelty upon which selection can act, which in turn determines their adaptive potential. Two examples clearly illustrate this adaptive potential: (i) the ability of helminths to parasitise single or multiple host species has arisen from free-living ancestors independently many times throughout their evolutionary history, with different species of helminth exploiting distinct mechanisms to invade and establish in their host, and (ii) widespread and frequent use of anthelmintic drugs to control parasites has rapidly selected for drug-resistant parasites. Only three classes of broad-spectrum anthelmintics are available; in veterinary animals (and particularly in livestock), resistance to all of classes including to multiple classes simultaneously has been documented in many helminths species throughout the world, in as little as a few years after introduction of the drug. In humans, there are increasing concerns that reduced efficacy of these same drugs is evidence of emerging resistance, which threatens to reverse gains from up to 30 years of successful treatment and parasite control. The genetic basis for this adaptation is, however, poorly understood. This major gap in our knowledge, largely due to the high genetic diversity and experimental intractability of most helminth species, limits our ability to understand these processes, which need to be overcome to successfully treat disease and predict outcomes of long-term control programmes.My work will identify the genetic mechanisms underpinning parasite adaptation. To do so, I will focus initially on the impact drug selection using ivermectin, a vitally important drug in human and animal health, has on the genetic diversity of Haemonchus contortus, a major economically important gastrointestinal parasite of livestock worldwide and a genetically tractable model used for drug discovery, vaccine development, and anthelmintic resistance research. Using a genetic cross between susceptible and ivermectin resistant H. contortus strains to control genetic diversity, together with high-throughput population and single-cell genomic approaches to sample genetic diversity over a multi-year evolution experiment, this research will dissect the interaction between genetic and phenotypic variation, and the impact that selection has on shaping this variation. Further, these data will show their potential for future adaptation, and identify evolutionary constraints that may be exploited for novel control interventions. More broadly, these data will inform practices to improve the health and welfare of animals exposed to parasites like H. contortus, and provide a novel experimental and theoretical framework toward understanding the adaptive potential of genetically intractable helminth species of human and veterinary medical importance