Co-evolutionary Genetics of Host-Parasite Interactions

宿主-寄生虫相互作用的共同进化遗传学

• 批准号: 10589864
• 负责人: NOAH K WHITEMAN
• 金额: $ 45.12万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-11 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10589864
• 关键词: Address; Aloral; Animal Model; Animals; Basic Science; Behavior; Biological; Biology; Butterflies; CRISPR/Cas technology; Cardiac Glycosides; Cells; Congestive Heart Failure; Detection; Development; Disease; Drosophila melanogaster; Evolution; Genes; Genetic; Genetic Models; Genomics; Goals; Human; Immune; Immune system; Individual; Isothiocyanates; Knock-in; Knowledge; Malignant Neoplasms; Mediating; Medical; Mission; Modeling; Mouse-ear Cress; Mutation; National Institute of General Medical Sciences; Natural Selections; Nature; Odorant Receptors; Organism; Parasite resistance; Parasites; Parkinson Disease; Pattern; Phase; Plant Model; Population; Process; Proteins; Public Health; Research; Resistance; Shapes; System; Technology; Tissues; Toxin; United States National Institutes of Health; Variant; Volatilization; Walking; base; common treatment; cytolethal distending toxin; flexibility; fly; foodborne; genome-wide; in vivo; interest; mustard oil; parasitism; therapy development; transmission process

PROJECT SUMMARY/ABSTRACT Long-lived and directly transmitted parasitic animals are among the most potent agents of natural selection known from human populations. Yet, there is a fundamental gap in our knowledge of the co-evolutionary mechanisms producing these patterns. This is, in part, because host-parasite interactions are notoriously difficult to study. Until remedied, progress toward understanding an elusive process that has profoundly shaped our biology is impeded. New model host-parasite systems are therefore critical for advancing the field. The long- term goal of our research is to develop and leverage new model host-parasite models for mechanistic studies of co-evolution. Over the past nearly four years of ESI MIRA support, we have made considerable progress toward dissecting the genomic basis of the evolution of parasitism and host specialization, and in determining the extent to which co-evolutionary interactions maintain genome-wide variation in host and parasite populations. The rationale is that parasitism evolved repeatedly in the lineage that includes the genetic model animal Drosophila melanogaster. Conveniently, these parasitic flies complete development in the genetic model plant Arabidopsis thaliana, facilitating in-depth mechanistic study. In addition to addressing our core objectives, the MIRA’s transformative flexibility allowed pursuit of risky new leads, resulting in a number of fundamental discoveries of broad interest to biologists. This included characterization of the first odorant receptors specific to volatile mustard oil toxins (isothiocyanates or ITCs) known in animals, the first use of CRISPR-Cas9 gene editing technology to fully retrace an adaptive walk in an animal (the mutations sufficient for resistance to cardiac glycoside toxins in monarch butterflies) using an in vivo knock-in approach, and identification of the first genes from animals known to encode cytolethal distending toxin (CDT) subunit B proteins, which is our model for the evolution of toxins used by human immune cells. These discoveries now form the basis of our proposed transition to EI MIRA support over the next five years. Our specific goal in the next phase of research is to identify the evolution and mechanistic bases of interactions between hosts and parasites that are mediated by three toxin classes: ITCs, cardiac glycosides, and CDTs. Three projects already underway that will address this goal are: (1) the evolution and mechanistic basis of toxin detection by parasites (ITCs), (2) the evolution and mechanistic basis of toxin resistance by parasites (ITCs and cardiac glycosides), and (3) the evolution and mechanistic basis of toxin co-option by the immune system (CTDs). This research is expected to inform our understanding of how toxins of

项目摘要/摘要 长寿和直接传播的寄生动物是自然选择最有效的因素之一。 从人类种群中获知。然而，我们对共同进化的认识存在一个根本性的差距。 产生这些图案的机制。这在一定程度上是因为宿主和寄生虫之间的相互作用是出了名的困难。 去学习。在得到补救之前，在理解一个难以捉摸的过程方面取得进展，这个过程深刻地塑造了我们的 生物学受到了阻碍。因此，新型寄主-寄生虫系统对于推动这一领域的发展至关重要。长的- 我们研究的长期目标是开发和利用新的模型宿主-寄生虫模型来进行机理研究 共同进化。在过去近四年的ESI Mira支持中，我们在以下方面取得了相当大的进展 解剖寄生和寄主专化进化的基因组基础，并确定其程度 共同进化的相互作用维持宿主和寄生虫种群的全基因组变异。这个 理论基础是，寄生在包括遗传模式动物果蝇在内的谱系中反复进化 黑猩猩。方便的是，这些寄生苍蝇在遗传模式植物拟南芥中完全发育 Taliana，便于深入的机理研究。除了解决我们的核心目标外，Mira的 变革性的灵活性允许追求高风险的新线索，导致了许多根本性的发现 引起了生物学家的广泛兴趣。这包括对第一种针对挥发性物质的气味受体的鉴定。 芥子油毒素(异硫氰酸酯或ITCs)已知在动物中，首次使用CRISPR-Cas9基因编辑 在动物身上完全追溯适应性行走的技术(足以抵抗心脏的突变 帝王蝶中的糖苷毒素)，并鉴定了第一个基因 来自已知编码细胞致死性扩张毒素(CDT)亚单位B蛋白的动物，这是我们的模型 人类免疫细胞使用的毒素的进化。这些发现现在构成了我们提议的过渡的基础 在未来五年向Ei Mira提供支持。我们在下一阶段研究的具体目标是确定 三种毒素介导的寄主与寄生虫相互作用的进化及其机制基础 分类：ITCs、强心苷和CDT。目前正在进行的三个项目将实现这一目标，它们是： (1)寄生虫检测毒素的进化和机理基础；(2)寄生虫检测毒素的进化和机理 寄生虫(ITCs和强心苷)的毒素抗性基础；(3)进化和机制基础 免疫系统(CTDS)对毒素的选择性。这项研究有望让我们了解到 毒物中的