The generation and maintenance of genetic novelty in helminth populations

蠕虫，通常被称为寄生虫，是一组生物体，它们利用各种各样的宿主和生活史策略，使其在几代人中持续存在。蠕虫感染的人和动物的兽医重要性，如伴侣和食品生产动物，是负责在其宿主的重大疾病负担，导致疼痛，残疾，发育迟缓，并在某些情况下，死亡在世界各地。在世界范围内，超过15亿人和无数动物在任何特定时间感染一种或多种蠕虫。因此，人类蠕虫感染是大规模药物施用运动的目标，并且在兽医环境中，数亿动物用驱虫药治疗以预防和/或治愈感染。驱虫药治疗蠕虫感染的重要性不可低估;伊维菌素作为驱虫药的发现和开发获得了2015年诺贝尔生理学或医学奖的认可。蠕虫在宿主内外生存和适应的能力在于它们产生和保持显著的遗传新奇的能力，选择可以发挥作用，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）蠕虫寄生单个或多个宿主物种的能力在其进化历史中多次独立地产生于自由生活的祖先，不同种类的蠕虫利用不同的机制入侵并在其宿主中定居，和（ii）广泛和频繁地使用驱虫药来控制寄生虫已经迅速地选择了抗药性寄生虫。只有三类广谱驱虫药可用;在兽医动物（特别是牲畜）中，在引入药物后短短几年内，已在世界各地的许多蠕虫物种中记录了对所有类别的耐药性，包括同时对多个类别的耐药性。在人类中，越来越多的人担心，这些药物的疗效降低是新出现的耐药性的证据，这可能会逆转长达30年的成功治疗和寄生虫控制的成果。然而，这种适应的遗传基础却知之甚少。我们知识的这一重大差距，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棘手性，限制了我们理解这些过程的能力，这些过程需要被克服以成功地治疗疾病和预测长期控制方案的结果。要做到这一点，我将首先集中在使用伊维菌素，在人类和动物健康的一个至关重要的药物选择的影响，对捻转血矛线虫的遗传多样性，一个主要的经济上重要的胃肠道寄生虫的牲畜世界各地和遗传上易于处理的模型用于药物发现，疫苗开发和抗蠕虫药的耐药性研究。利用敏感和伊维菌素抗性H。contortus菌株来控制遗传多样性，再加上高通量人口和单细胞基因组方法来采样遗传多样性在多年的进化实验，这项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化的影响。此外，这些数据将显示其未来适应的潜力，并确定可用于新的控制干预措施的进化限制。更广泛地说，这些数据将为改善暴露于H。contortus，并提供了一个新的实验和理论框架，以了解适应潜力的遗传难治性蠕虫物种的人类和兽医医学的重要性

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