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

项目摘要 传染病研究的一个中心目标是确定决定一个人的 对寄生虫的易感性。生物医学研究在实现这一目标方面取得了实质性进展 建立检测寄生虫抗性相关等位基因的分子和遗传学方法 和寄主健康。在包括人类在内的许多有机体中追踪这些等位基因揭示了一种 潜在问题：在一个环境中，等位基因可能会强烈地预测寄生虫的抵抗力，但不会 其他的，或者对抗一种寄生虫株而不是其他寄生虫株。这种对上下文的依赖可能解释了为什么 基因组研究很少能够确定一致地解释疾病的等位基因。 人类的易感性。此外，中国对寄生虫的抗性存在巨大的遗传多样性。 寄主群体，而这种多样性在少数用于识别 模式生物中的等位基因。因此，要全面了解对人类健康有影响的等位基因 对于寄生虫的抗性，我们必须考虑到目前存在的遗传多样性和环境复杂性 在宿主遇到寄生虫的自然环境中。在接下来的五年里，我的研究 实验室将通过描述寄生虫抗性的遗传基础来满足这一需求 使用从自然中采样的不同宿主和寄生虫基因类型的环境背景。我的实验室 我们的团队非常适合这项工作：我们拥有线虫秀丽线虫和线虫的专业知识 它最流行的自然寄生虫是细小孢子虫。这款功能强大的型号 该系统使我们能够快速、廉价地进行高度重复的实验和基因组 分析以检查不同背景下的遗传变异。收集野生线虫分离物的最新努力 寄生虫菌株为我们提供了必要的自然变异的广泛样本 进球。在这里，我建议1)描述在自然界中导致寄生虫抗性的等位基因 使用高通量表型、全基因组关联调查和高通量 基于野生线虫全序列公共集合的分辨率数量性状定位 基于多个野生亲本的基因分型(&gt；300)和重组自交系。然后我提议 使用实验进化、表型图谱和转基因宿主系来：2)评估影响 寄生虫基因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化的敏感性，特别是在微生物饲料和 人口密度。这项拟议的工作构成了我的研究计划的基础，目标是 建立确定寄生虫的等位基因多样性的通用框架 并在现实世界环境中评估它们对宿主健康的贡献。这项工作将 支持利用遗传数据预测个人和人口健康的努力。

Project Summary A central goal of infectious disease research is to identify the genes that determine an individual’s susceptibility to parasites. Biomedical research has made substantial progress towards this goal by establishing molecular and genetic approaches for detecting alleles associated with parasite resistance and host health. Pursuing these alleles across many organisms, including humans, has revealed an underlying problem: an allele 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 alleles that consistently explain disease susceptibility in humans. In addition, there is immense genetic diversity for parasite resistance in host populations, and this diversity is not represented in the few inbred lab lines used to identify alleles in model organisms. Therefore, to gain a general understanding of the alleles that matter for parasite resistance, we must account for the genetic diversity and environmental complexity present in the natural settings in which hosts encounter their parasites. In the next five years, research in my lab will address 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 is well-positioned for this work: we have expertise in the nematode Caenorhabditis elegans and its most prevalent natural parasite, the microsporidia Nematocida parisii. This powerful model system enables us to quickly and cheaply perform highly replicated experiments and genomic analyses to examine genetic variants across contexts. Recent efforts to collect wild C. elegans isolates and parasite strains have provided us with the broad sampling of natural variation necessary for our goal. Here, I propose to 1) characterize the alleles that contribute to parasite resistance in natural populations using high-throughput phenotyping, genome-wide association surveys, and high- resolution quantitative trait mapping based on public collections of fully-sequenced wild C. elegans genotypes (>300) and recombinant inbred lines based on multiple wild parents. I then propose to use experimental evolution, phenotype mapping, and transgenic host lines to: 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, specifically in microbial diet and population density. This proposed work forms the foundation of my research program targeted at establishing general frameworks for identifying the diversity of alleles that can determine parasite resistance and evaluating their contribution to host health in real world settings. This work will support efforts to use genetic data to predict the health of individuals and populations.