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：
10579336
负责人：
Erik Christian Andersen
金额：
$ 65.32万
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 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10579336
关键词：
Affect Anatomy 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 Persons Pesticides Phenotype Population Property Quantitative Genetics Quantitative Trait Loci Recombinants Research Resolution Resources Risk Rodent Scheme Signal Transduction Source System Techniques Toxic Environmental Substances Toxin Variant comparative cost environmental chemical experimental study fitness gene conservation gene discovery genetic approach genetic resource genetic variant genome editing genome wide association study genomic locus high throughput screening improved innovation life history model organism 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.

项目摘要：接触环境化学物质是主要的健康风险。不幸的是，毒素的不利影响由于遗传差异未知，人口中的个体暴露在人群中有所不同。更好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健康影响。很难识别这些因素，因为人类全基因组的关联经常研究缺乏必要的统计能力和控制的毒素暴露。因此，我们将使用定义 round虫秀丽隐杆线虫的人口范围差异可实现毒素的精确测量单细胞生物的尺度和统计能力的反应，但具有保守的分子，细胞，和后生动物的发展特性。在AIM 1中，我们将确定遗传基因座的潜在差异对30种多种毒素的反应，包括金属/金属，线粒体毒素，农药和火焰阻燃剂。我们将使用低成本，高通量，在不同个体中定义有效的毒素剂量以及高准确的生长和生育测定法。然后，我们将定义整个人口的变化对这30种毒素的反应，并使用这些数据使用两个映射面板：（1）Cendr-秀丽隐杆线虫自然多样性资源，一组500株代表该物种几乎所有已知的遗传变异，（2）Cemee-秀丽隐杆线虫多元实验 Evolution面板，一组1000个重组近交系，可以映射到单个基因的分辨率。在AIM 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。我们将使用最新的毒素反应差异和遗传变异之间的因果关系繁殖和基因组编辑技术。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异的分子基础。在AIM 3中，我们将阐明通过在另外两个Caenorhabditis中绘制毒素反应的毒素反应变化的保守机制与小鼠和人类一样，在遗传上与众不同的物种。创新的比较定量性状基因座分析将确保鉴定出现的毒素反应变化来源在多个进化谱系中（因此可以预见）收集（因此可以预见）。我们将通过进一步将我们的映射结果与果蝇，啮齿动物和人类的映射结果进行比较，以识别保守的结果负责毒素反应变化的途径。我们的Caenorhabditis遗传资源具有变异，等位基因频率和表型效应与人类类似，提供了一个框架来发现基因和变体的特征是人类毒素反应差异的基础。确实，数十年秀丽隐杆线虫的研究已经确定了无数的广泛保守分子机制的例子潜在的信号传导，基因调节和代谢，表明毒素反应机制尽管生活史和解剖结构明显差异，但这里发现的人仍将扩展到人类。

项目成果

期刊论文数量（15）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Natural variation in the sequestosome-related gene, sqst-5, underlies zinc homeostasis in Caenorhabditis elegans.

DOI：
10.1371/journal.pgen.1008986
发表时间：
2020-11
期刊：
PLoS genetics
影响因子：
4.5
作者：
Evans KS;Zdraljevic S;Stevens L;Collins K;Tanny RE;Andersen EC
通讯作者：
Andersen EC

Natural genetic variation as a tool for discovery in Caenorhabditis nematodes.

DOI：
10.1093/genetics/iyab156
发表时间：
2022-01-04
期刊：
Genetics
影响因子：
3.3
作者：
Andersen EC;Rockman MV
通讯作者：
Rockman MV

easyXpress: An R package to analyze and visualize high-throughput C. elegans microscopy data generated using CellProfiler.

DOI：
10.1371/journal.pone.0252000
发表时间：
2021
期刊：
PloS one
影响因子：
3.7
作者：
Nyaanga J;Crombie TA;Widmayer SJ;Andersen EC
通讯作者：
Andersen EC

C. elegans toxicant responses vary among genetically diverse individuals.

DOI：
10.1016/j.tox.2022.153292
发表时间：
2022-09
期刊：
TOXICOLOGY
影响因子：
4.5
作者：
Widmayer, Samuel J.;Crombie, Timothy A.;Nyaanga, Joy N.;Evans, Kathryn S.;Andersen, Erik C.
通讯作者：
Andersen, Erik C.

Evaluating the power and limitations of genome-wide association studies in Caenorhabditis elegans.