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:
- 金额:$ 65.32万
- 依托单位:
- 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:
- 关键词:AffectAnatomyArchitectureArsenicBiological AssayBiological ModelsBreedingCRISPR/Cas technologyCaenorhabditisCaenorhabditis elegansCandidate Disease GeneCellsCharacteristicsChemical ExposureChromosome MappingDataDevelopmentDoseDrosophila genusEnsureEvolutionExposure toFeeding behaviorsFertilityFlame RetardantsGene Expression ProfilingGene Expression RegulationGene FrequencyGenesGeneticGenetic VariationGenomicsGenotypeGrowthHealthHeavy MetalsHeritabilityHumanHuman GenomeInbreedingIndividualInterventionKnowledgeLeadLearningMapsMeasurementMeasuresMetabolismMetalsMitochondriaModelingMolecularMusNematodaOrganismOutcomePathway interactionsPersonsPesticidesPhenotypePopulationPropertyQuantitative GeneticsQuantitative Trait LociRecombinantsResearchResolutionResourcesRiskRodentSchemeSignal TransductionSourceSystemTechniquesToxic Environmental SubstancesToxinVariantcomparativecostenvironmental chemicalexperimental studyfitnessgene conservationgene discoverygenetic approachgenetic resourcegenetic variantgenome editinggenome wide association studygenomic locushigh throughput screeningimprovedinnovationlife historymodel organismnext generationnovelpredicting responseresponsetherapy designtool
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:
- 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:
- 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:
- 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:
- 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:
- 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.
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Erik Christian Andersen其他文献
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{{ truncateString('Erik Christian Andersen', 18)}}的其他基金
Genetic and genomic tools for C. briggsae research
用于 C. briggsae 研究的遗传和基因组工具
- 批准号:
10371532 - 财政年份:2022
- 资助金额:
$ 65.32万 - 项目类别:
Genetic and genomic tools for C. briggsae research
用于 C. briggsae 研究的遗传和基因组工具
- 批准号:
10582658 - 财政年份:2022
- 资助金额:
$ 65.32万 - 项目类别:
Discovery of novel benzimidazole resistance mechanisms
发现新的苯并咪唑耐药机制
- 批准号:
10190824 - 财政年份:2020
- 资助金额:
$ 65.32万 - 项目类别:
Discovery of Novel Benzimidazole Resistance Mechanisms
新型苯并咪唑耐药机制的发现
- 批准号:
10895749 - 财政年份:2020
- 资助金额:
$ 65.32万 - 项目类别:
Discovery of novel benzimidazole resistance mechanisms
发现新的苯并咪唑耐药机制
- 批准号:
10438771 - 财政年份:2020
- 资助金额:
$ 65.32万 - 项目类别:
Discovery of novel benzimidazole resistance mechanisms
发现新的苯并咪唑耐药机制
- 批准号:
10029488 - 财政年份:2020
- 资助金额:
$ 65.32万 - 项目类别:
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
- 批准号:
10328239 - 财政年份:2019
- 资助金额:
$ 65.32万 - 项目类别:
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
- 批准号:
10088449 - 财政年份:2019
- 资助金额:
$ 65.32万 - 项目类别:
Large scale nutrigenetics and genomics in a tractable metazoan model
易处理的后生动物模型中的大规模营养遗传学和基因组学
- 批准号:
9761523 - 财政年份:2017
- 资助金额:
$ 65.32万 - 项目类别:
Large scale nutrigenetics and genomics in a tractable metazoan model
易处理的后生动物模型中的大规模营养遗传学和基因组学
- 批准号:
9423155 - 财政年份:2017
- 资助金额:
$ 65.32万 - 项目类别:
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