Discovery of conserved molecular mechanisms underlying population-wide variation in toxin responses

发现人群毒素反应差异的保守分子机制

基本信息

批准号：
10088449
负责人：
Erik Christian Andersen
金额：
$ 69.44万
依托单位：
NORTHWESTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10088449
关键词：
Affect Anatomy Animal Model Architecture Arsenic Biological Assay Biological Models Breeding CRISPR/Cas technology Caenorhabditis Caenorhabditis elegans Candidate Disease Gene Cells Characteristics Chemical Exposure Chromosome Mapping Data Development Dose Drosophila genus Ensure Evolution Exposure to Feeding behaviors Fertility Flame Retardants Gene Expression Profiling Gene Expression Regulation Gene Frequency Genes Genetic Genetic Variation Genomics Genotype Growth Health Heavy Metals Heritability Human Human Genome Inbreeding Individual Intervention Knowledge Lead Learning Maps Measurement Measures Metabolism Metals Mitochondria Modeling Molecular Mus Nematoda Organism Outcome Pathway interactions Pesticides Phenotype Population Problem Solving Property Quantitative Genetics Quantitative Trait Loci Recombinants Research Resolution Resources Risk Rodent Scheme Signal Transduction Source Structure of molecular layer of cerebellar cortex System Techniques Toxic Environmental Substances Toxin Variant comparative cost environmental chemical experimental study fitness gene discovery genetic approach genetic resource genetic variant genome editing genome wide association study genomic locus high throughput screening improved innovation life history next generation novel predicting response response therapy design tool

项目摘要

Project summary: Exposure to environmental chemicals is a major health risk. Unfortunately, the detrimental impacts of toxin exposure vary among individuals in a population because of unknown genetic differences. With a better understanding of how our genetics influence toxin response, we can more accurately predict detrimental health effects. It is difficult to identify these factors because human genome-wide association studies often lack the necessary statistical power and controlled toxin exposures. For this reason, we will use defined population-wide variation in the roundworm Caenorhabditis elegans to enable precise measurements of toxin responses at the scale and statistical power of single-cell organisms but with conserved molecular, cellular, and developmental properties of a metazoan. In Aim 1, we will identify genetic loci underlying variation in response to 30 diverse toxins, including metals/metalloids, mitochondrial toxins, pesticides, and flame retardants. We will define effective toxin doses across diverse individuals using low-cost, high-throughput, and high-accuracy assays of growth and fertility. Then, we will define the population-wide variation in response to these 30 toxins and use these data to map toxin-response differences to genes using two mapping panels: (1) CeNDR - the C. elegans Natural Diversity Resource, a set of 500 strains representing nearly all known genetic variation for the species, and (2) CeMEE - the C. elegans Multiparental Experimental Evolution panel, a set of 1000 recombinant inbred lines that enable mapping to the resolution of single genes. In Aim 2, we will identify specific genetic variants and pathways affecting toxin-response variation. We will define causal relationships between toxin response differences and genetic variants using state-of-the-art breeding and genome-editing techniques. Then, we will use gene expression analyses and hypothesis- directed experiments to determine the molecular basis of toxin-response variation. In Aim 3, we will elucidate conserved mechanisms of toxin-response variation by mapping toxin responses in two other Caenorhabditis species that are as genetically different from each other as mice and humans. An innovative comparative quantitative trait locus analysis will ensure identification of sources of toxin-response variation that arise convergently (and therefore predictably) in multiple evolutionary lineages. We will extend this approach by further comparing our mapping results to those from Drosophila, rodents, and humans, identifying conserved pathways responsible for toxin-response variation. Our Caenorhabditis genetic resources have levels of variation, allele frequencies, and phenotypic effects similar to humans, providing a framework to discover the characteristics of genes and variants that underlie differences in human toxin responses. Indeed, decades of research in C. elegans have identified countless examples of widely conserved molecular mechanisms underlying signaling, gene regulation, and metabolism, suggesting that the toxin-response mechanisms discovered here will extend to humans despite overt differences in life history and anatomy.

项目概要：接触环境化学品是一个主要的健康风险。不幸的是，毒素的有害影响由于未知的遗传差异，人群中个体的暴露程度存在差异。有了更好的了解我们的遗传学如何影响毒素反应，我们可以更准确地预测有害的健康影响。确定这些因素很困难，因为人类全基因组关联研究经常缺乏必要的统计能力和受控的毒素暴露。因此，我们将使用定义的秀丽隐杆线虫种群范围内的变异使得毒素的精确测量成为可能单细胞生物体的规模和统计能力的反应，但具有保守的分子、细胞、和后生动物的发育特性。在目标 1 中，我们将确定潜在变异的遗传位点对 30 种不同毒素的反应，包括金属/类金属、线粒体毒素、杀虫剂和火焰阻燃剂。我们将使用低成本、高通量、以及生长和生育力的高精度测定。然后，我们将定义人口范围内的差异对这 30 种毒素的反应，并使用这些数据将毒素反应差异映射到基因，使用两个绘图小组：(1) CeNDR - 线虫自然多样性资源，一组 500 个菌株，代表几乎所有已知的物种遗传变异，以及 (2) CeMEE - 线虫多亲实验 Evolution panel，一组 1000 个重组自交系，可实现单基因分辨率的定位。在目标 2 中，我们将确定影响毒素反应变异的特定遗传变异和途径。我们将使用最先进的技术定义毒素反应差异与遗传变异之间的因果关系育种和基因组编辑技术。然后，我们将使用基因表达分析和假设- 定向实验以确定毒素反应变化的分子基础。在目标 3 中，我们将阐明通过绘制另外两种秀丽隐杆线虫的毒素反应图谱来确定毒素反应变异的保守机制物种之间的基因差异就像老鼠和人类一样。创新比较数量性状基因座分析将确保识别出现的毒素反应变异的来源在多个进化谱系中趋同（因此是可预测的）。我们将通过以下方式扩展这种方法进一步将我们的图谱结果与果蝇、啮齿动物和人类的图谱结果进行比较，确定保守的负责毒素反应变化的途径。我们的秀丽隐杆线虫遗传资源水平为与人类相似的变异、等位基因频率和表型效应，为发现造成人类毒素反应差异的基因和变异的特征。确实，几十年来对线虫的研究已经发现了无数广泛保守的分子机制的例子潜在的信号传导、基因调控和代谢，表明毒素反应机制尽管生活史和解剖结构存在明显差异，但这里发现的新发现仍将适用于人类。