A general test of the genetic basis of parasite resistance across genetic and environmental contexts

项目摘要 传染病研究已经优先确定赋予抵抗力的基因。 传染病病原体。在包括人类在内的多种生物体中寻找这些基因， 揭示了一个基本的障碍：一个基因可能强烈预测寄生虫在一个环境中的抵抗力 而不是其他的，或者针对一种寄生虫菌株而不是其他的。这种情境依赖性可以解释 为什么基因组调查很少能够识别出能够持续解释大量 人类抗病能力的变异。为了对重要的基因有一个大致的了解， 为了抵抗寄生虫，我们必须控制和考虑自然环境的复杂性， 宿主遇到寄生虫的环境。我的父母奖通过以下方式满足了这一需求 利用遗传和环境背景表征寄生虫抗性的遗传基础 从自然界采集的多种宿主和寄生虫基因型。我的实验组使用了一个强大的模型 系统-线虫秀丽隐杆线虫及其天然寄生虫显微镜 这使我们能够快速和廉价地进行高度重复的实验 和基因组分析来检查不同背景下的遗传变异。我们应用高通量 表型分析、全基因组关联作图、实验进化和转基因方法， 1)确定解释自然种群中寄生虫抗性变异的基因座，2）评估 寄生虫基因型对寄生虫抗性遗传变异表达的影响，以及3） 检测抗性等位基因对相关环境变异的敏感性。我的影响 亲本奖励基本上取决于我们快速表现许多基因型的能力， 在最小化变化的条件下，在上下文中和上下文中纳入重要的复制 非焦点因素引起的。因此，我们要求对这一家长奖进行补充， 为我们的大颗粒分选机购买自动进样器附件，这将增加重复性， 我们的高通量表型分析工作的准确性和可重复性。该补充将直接 扩大我们正在进行的项目对科学界的影响，以及提供长期的 支持我的研究计划和我的研究社区。

Project Summary Infectious disease research has made it a priority to identify the genes that confer resistance to infectious disease agents. Pursuing these genes in a diversity of organisms, including humans, has revealed a fundamental obstacle: a gene may strongly predict parasite resistance in one environment but not others, or against one parasite strain but not others. This context-dependence might explain why genomic surveys have rarely been able to identify genes that consistently explain substantial variation in disease resistance in humans. To gain a general understanding of the genes that matter for parasite resistance, we must both control and account for the complexities of the natural environments in which hosts encounter their parasites. My parent award addresses this need by characterizing the genetic basis of parasite resistance across genetic and environmental contexts using diverse host and parasite genotypes sampled from nature. My lab group uses a powerful model system – the nematode Caenorhabditis elegans and its natural parasite the microscopiridia Nematocida parisii - that enables us to quickly and cheaply perform highly replicated experiments and genomic analyses to examine genetic variants across contexts. We apply high-throughput phenotyping, genome-wide association mapping, experimental evolution, and transgenic methods to 1) identify the loci that explain variation in parasite resistance in natural populations, 2) evaluate the impact of parasite genotype on the expression of genetic variation for parasite resistance, and 3) examine the sensitivity of resistance alleles to relevant environmental variation. The impact of my parent award rests fundamentally upon our ability to rapidly phenotype many genotypes, incorporating significant replication within and across contexts in conditions that minimize variation arising from non-focal factors. Therefore, we are requesting a supplement to this parent award to purchase an autosampler attachment for our large particle sorter that will increase the replication, accuracy, and repeatability of our high-throughput phenotyping efforts. This supplement will directly augment the impact of our ongoing projects on the scientific community, as well as provide long-term support to my research program and my research community.