Mining natural infection variation to find the genetic basis of coevolution between vertebrate hosts and helminth parasites

项目摘要/摘要 蠕虫(即寄生蠕虫)感染所有脊椎动物类群。主机通常会发展为阻止、清除或限制 感染的负面影响，寄生虫进化以躲避或操纵宿主生理。数不胜数 已知分子和细胞通路调节脊椎动物宿主和蠕虫之间的相互作用。 寄生虫，但人们对免疫和传染性的进化如何影响自然变异知之甚少。 寄生虫感染。关于导致免疫进化差异的特定遗传差异的数据如下 同样有限。在接下来的五年里，我的实验室将描述遗传机制和进化史 三刺鱼是一种具有丰富生态和遗传资源的小鱼之间的共同进化 (Gastersteus Aculeatus)和它的一种寄生虫。这项工作由基于实验的协议来促进 高效地与绦虫交叉，将刺鱼暴露在这些病原体的控制剂量下，共培养宿主和 体外免疫细胞，寄主免疫力和寄生虫存活率的测定。我们不仅可以识别和测量 影响感染特异性和强度的可遗传特征，但也应用现代遗传方法 剖析这种自然选择变异背后的分子机制。我们的初步数据显示， 三条刺鱼反复进化以阻止最初的建立和随后的增长 但抗药性的机制因种群而异。绦虫也进化成了中和 本地主机的防御，最终导致主机子集的专门化。我们将使用Forward 遗传学定位与病原体驱动的寄主进化相关的染色体基因座，同时杂交出现分歧 鞭虫种群将揭示由于寄主驱动的选择而进化的基因座。这项工作将得到补充 通过对候选基因和分子途径的药理学和转基因操作，以及 探索自然环境，我们将使用实验性移植和时间序列数据来理解 共同进化如何因生态和空间限制而变化。也许最令人兴奋的是，有几个 关系密切的刺鱼物种和鞭虫物种，尽管数百万年来存在分歧，但它们仍然存在 相互干扰的，这使我们能够表征共同进化的遗传学在微观和 宏观进化的时间尺度。

Project Summary/Abstract Helminths (i.e., parasitic worms) infect all vertebrate taxa. Hosts generally evolve to block, purge, or limit the negative effects of infection, and parasites evolve to hide from or manipulate host physiology. Numerous molecules and cellular pathways are known to modulate interactions between vertebrate hosts and helminth parasites, but little is known about how the evolution of immunity and infectivity influences natural variation in parasite infections. Data on the particular genetic differences that underlie evolved differences in immunity are similarly limited. Over the next five years, my lab will describe the genetic mechanisms and evolutionary history of coevolution between a small fish with abundant ecological and genetic resources, the threespine stickleback (Gasterosteus aculeatus), and one of its cestode parasites. This work is facilitated by lab-based protocols to efficiently intercross cestodes, expose sticklebacks to controlled doses of these pathogens, co-culture host and immune cells in vitro, and assays of host immunity and parasite viability. We can not only identify and measure heritable traits that affect infection specificity and intensity, but also apply modern genetic approaches to dissect the molecular mechanisms underlying this naturally selected variation. Our preliminary data show that threespine sticklebacks repeatedly evolved to block the initial establishment and subsequent growth of cestodes, but that the mechanisms of resistance vary across populations. Cestodes also evolved to counteract the defenses of their local hosts, eventually leading to specialization on a subset of hosts. We will use forward genetics to map the chromosomal loci associated with pathogen-driven host evolution, while crossing diverged cestode populations will uncover loci evolving due to host-driven selection. This work will be complemented with pharmacological and transgenic manipulations of candidate genes and molecular pathways, as well as forays into natural settings where we will use both experimental transplants and time-series data to understand how coevolution varies due to ecological and spatial constraints. Perhaps most exciting, there are several closely related stickleback species and cestode species that, despite millions of years of divergence, remain interfertile, and which enable us to characterize the genetics of coevolution across both micro- and macroevolutionary timescales.