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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.

项目总结:

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

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

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

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

DOI：
10.1093/g3journal/jkac114
发表时间：
2022-07-06
期刊：
G3 (Bethesda, Md.)
影响因子：
0
作者：
通讯作者：

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.