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

基本信息

批准号：
10649577
负责人：
Amanda K Gibson
金额：
$ 39.73万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
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

项目摘要

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.

项目概要传染病研究的一个中心目标是确定决定个体的基因生物医学研究已在实现这一目标方面取得了实质性进展。建立分子和遗传学方法来检测与寄生虫抗性相关的等位基因在包括人类在内的许多生物体中追踪这些等位基因，揭示了一个事实。根本问题：等位基因可能强烈预测一种环境中的寄生虫抗性，但不能或针对一种寄生虫菌株而不是其他菌株，这种环境依赖性可能可以解释原因。基因组调查很少能够识别能够一致解释疾病的等位基因此外，人类对寄生虫的抵抗力存在巨大的遗传多样性。宿主群体，并且这种多样性并没有在用于识别的少数近交实验室系中得到体现因此，要对重要的等位基因有一个总体的了解。寄生虫抗性，我们必须考虑目前的遗传多样性和环境复杂性在接下来的五年里，我将在宿主遇到寄生虫的自然环境中进行研究。实验室将通过表征跨遗传和寄生虫抗性的遗传基础来满足这一需求。使用从自然界采样的不同宿主和寄生虫基因型的环境背景。小组在这项工作中处于有利地位：我们拥有线虫秀丽隐杆线虫方面的专业知识，它最常见的天然寄生虫是微孢子虫 Nematocida parisii 这种强大的模型。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。最近收集野生秀丽隐杆线虫分离株的努力。和寄生虫菌株为我们提供了我们的自然变异所必需的广泛样本在这里，我建议 1）描述自然环境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于全测序野生线虫公共收藏的分辨率数量性状图谱然后我建议基于多个野生亲本的基因型（> 300）和重组自交系。使用实验进化、表型作图和转基因宿主系来：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，特别是微生物饮食和这项拟议的工作构成了我针对人口密度的研究计划的基础。建立确定寄生虫等位基因多样性的通用框架这项工作将在现实世界中评估它们对宿主健康的贡献。支持使用遗传数据来预测个人和人群的健康状况。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Contrasting parasite-mediated reductions in fitness within versus between patches of a nematode host.

DOI：
10.1111/evo.14521
发表时间：
2022-07
期刊：
Evolution; international journal of organic evolution
影响因子：
0
作者：
通讯作者：

A diverse parasite pool can improve effectiveness of biological control constrained by genotype-by-genotype interactions.

DOI：
10.1111/eva.13501
发表时间：
2022-12
期刊：
Evolutionary applications
影响因子：
4.1
作者：
通讯作者：

A simple method to dramatically increase C. elegans germline microinjection efficiency.

一种显着提高秀丽隐杆线虫种系显微注射效率的简单方法。

DOI：
10.1101/2023.03.23.533855
发表时间：
2023
期刊：
bioRxiv : the preprint server for biology
影响因子：
0
作者：
Gibney,TheresaV;Favichia,Michelle;Latifi,Laila;Medwig-Kinney,TaylorN;Matus,DavidQ;McIntyre,DanielC;Arrigo,AngeloB;Branham,KendallR;Bubrig,LouisT;Ghaddar,Abbas;Jiranek,JulianaA;Liu,KendraE;Marcucci,CharlesG;Porter,Rober
通讯作者：
Porter,Rober

Genetic diversity and disease: The past, present, and future of an old idea.