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

跨越遗传和环境背景的寄生虫抗性遗传基础的一般测试

• 批准号: 10027549
• 负责人: Amanda K Gibson
• 金额: $ 39.7万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10027549
• 关键词: Address; Alleles; Animal Model; Biological Models; Biomedical Research; Caenorhabditis elegans; Collection; Communicable Diseases; Data; Dependence; Diet; Disease susceptibility; Environment; Epidemiologist; Evolution; Face; Foundations; Genes; Genetic; Genetic Variation; Genomics; Genotype; Goals; Health; Human; Inbreeding; Individual; Infection; Infectious Diseases Research; Knowledge; Medical; Microsporidia; Molecular Genetics; Nature; Nematoda; Organism; Parasite resistance; Parasites; Parents; Phenotype; Population; Population Density; Population Heterogeneity; Positioning Attribute; Predisposition; Recombinants; Research; Research Personnel; Resistance; Resolution; Resources; Risk Estimate; Sampling; Surveys; Testing; Transgenic Organisms; Variant; Work; base; experimental study; gene therapy; genetic approach; genetic variant; genome wide association study; microbial; programs; resistance allele; trait

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.

项目摘要 传染病研究的一个中心目标是确定决定个体疾病的基因。 对寄生虫的易感性。生物医学研究已经朝着这一目标取得了实质性进展， 建立检测寄生虫抗性相关等位基因的分子和遗传学方法 宿主健康。在包括人类在内的许多生物体中追踪这些等位基因，已经揭示了一种新的基因。 潜在的问题：等位基因可能强烈预测寄生虫在一个环境中的抵抗力， 或者针对一种寄生虫菌株而不是其他菌株。这种情境依赖性或许可以解释为什么 基因组调查很少能够确定等位基因，一贯解释疾病 人类的易感性此外，在寄生虫抗性方面存在巨大的遗传多样性， 宿主种群，这种多样性并不代表在少数近交实验室品系用于鉴定 模式生物中的等位基因。因此，为了获得对重要的等位基因的一般理解， 寄生虫的抵抗力，我们必须考虑到遗传多样性和环境的复杂性 在自然环境中，宿主遇到了他们的寄生虫。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， 环境背景下使用不同的主机和寄生虫的基因型从自然界采样。我的实验室 该集团在这项工作中处于有利地位：我们拥有线虫秀丽隐杆线虫的专业知识， 其最普遍的天然寄生虫，杀线虫微孢子虫Parisii。这个强大的模型 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。最近的努力收集野生C。秀丽线虫分离株 和寄生虫菌株为我们提供了广泛的自然变异样本， 目标.在这里，我建议1）描述自然界中有助于寄生虫抗性的等位基因， 使用高通量表型分析、全基因组关联调查和高通量基因组分析， 分辨率的数量性状定位的基础上，公共收集的全测序野生C。elegans 基因型（>300）和基于多个野生亲本的重组近交系。我建议 使用实验进化、表型作图和转基因宿主系：2）评估影响 寄生虫基因型对寄生虫抗性遗传变异表达的影响，以及3）检查 抗性等位基因对相关环境变化的敏感性，特别是在微生物饮食中， 人口密度这项拟议的工作构成了我的研究计划的基础， 建立鉴定等位基因多样性的一般框架， 耐药性和评估它们在真实的世界环境中对宿主健康的贡献。这项工作将 支持利用遗传数据预测个人和群体健康的努力。