Linking genomic, physiological, and behavioral responses using a Drosophila model of heavy metal stress

使用重金属应激的果蝇模型将基因组、生理和行为反应联系起来

• 批准号: 10283505
• 负责人: Elizabeth Everman
• 金额: $ 9万
• 依托单位: UNIVERSITY OF KANSAS LAWRENCE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10283505
• 关键词: Adult; Alleles; Bar Codes; Behavior; Behavioral; Behavioral Genetics; Biological Assay; Biological Models; Cadmium; Candidate Disease Gene; Cessation of life; Chromosome Mapping; Communities; Complex; Copper; Coupled; DNA Resequencing; Data; Decision Making; Desire for food; Detection; Development; Disease; Drosophila genus; Drosophila melanogaster; Environmental Health; Evolution; Exposure to; Gene Expression; Gene Frequency; Generations; Genes; Genetic; Genetic Models; Genetic Risk; Genetic Variation; Genomics; Health; Heavy Metals; Human; Infrastructure; Investigation; Lead; Learning; Learning Disabilities; Life; Link; Manganese; Measures; Memory; Metal exposure; Metals; Modeling; Morbidity - disease rate; Natural Resistance; Nervous System Physiology; Neurologic; Organism; Pathology; Pathway interactions; Phase; Phenotype; Physiological; Physiology; Pollution; Population; Poverty; Predisposition; Process; Quantitative Trait Loci; RNA; Recording of previous events; Research; Resistance; Resources; Risk; Stress; Syndrome; System; Testing; Time; Toxic effect; Validation; Variant; Whole Organism; Work; Zinc; acute toxicity; behavior influence; behavioral genomics; behavioral response; copper poisoning; disability; endophenotype; environmental stressor; experimental study; fly; gene environment interaction; gene expression variation; genetic architecture; genetic risk factor; genetic variant; genome sequencing; human disease; innovation; insight; interest; large datasets; life history; low socioeconomic status; metal metabolism; metal poisoning; neglect; nervous system disorder; novel; pollutant; preference; pressure; racial disparity; response; stressor; tool; trait; transcriptome sequencing; whole genome

Contact PD/PI: Everman, Elizabeth PROJECT SUMMARY Heavy metal pollution has pervasive environmental, health, and evolutionary impacts. In humans, health risks of heavy metals ranging from permanent neurological disease to increased morbidity of degenerative syndromes are exacerbated by poverty and fragile community infrastructure. Physiological responses to heavy metals including lead, cadmium, and copper have complex genetic architectures, and several heavy metals are known to hinder learning and alter behavior. However, these behavioral and physiological responses to metal stress are often considered in isolation, neglecting the specific genetic relationship between metal toxicity and behavioral response to metal stress. My primary objective is to dissect and characterize this whole organism heavy metal response by taking an integrative approach to examine the genetic basis of the relationship between physiological, behavioral, and evolutionary responses to heavy metal stress. The elite genetic model Drosophila melanogaster is ideal for my research because it shares many heavy metal-responsive genes with humans, it is extremely facile to conduct large-scale phenotyping assays, and an enormous plethora of sophisticated tools are available to facilitate in-depth behavioral and genomic experiments. I treat copper as my model heavy metal because, although required at low levels for normal development and physiological function, it is a common heavy metal pollutant that is metabolized and bioaccumulated by genes that also interact with lead, manganese, zinc, and cadmium. With Aim 1, I will disentangle the genetic link between physiological and behavioral responses to copper stress using a large mapping panel of genetically stable strains and combining large-scale screens of multiple behavioral traits with physiological data collected across multiple life stages. With Aim 2, I will characterize genetic and coevolutionary responses to copper selection in multiple populations derived from high and low copper resistance natural populations. Aim 2 will involve an evolve and resequencing (E&R) approach coupled with bulk RNA barcoding and sequencing (BRB-seq) to track the dynamic shifts in allele frequencies and gene expression through the course of artificial selection for copper resistance. Investigation of the evolutionary processes that lead to complex trait variation has great biomedical significance as we seek to understand the gene-by-environment interactions, genetic constraints, and genetic risk factors that contribute to increased susceptibility to toxic heavy metal exposure in human populations. This integrative approach leverages QTL mapping, whole genome and RNA-seq, sophisticated functional validation tools available for the D. melanogaster model system, and experimental evolution. This work will ultimately allow for the characterization of genetic variation in chemosensory ability, traits related to decision making, and neurological function in response to copper stress in diverse synthetic and naturally derived genetic backgrounds. Together, these approaches will provide critical insight into the interconnectedness of multiple response traits, while also illuminating genetic factors that influence behavioral and learning disabilities linked to metal poisoning.

联系PD/PI：Everman，Elizabeth 项目摘要 重金属污染具有普遍的环境，健康和进化影响。在人类中，健康风险 重金属从永久神经疾病到变性综合征的发病率增加 贫穷和脆弱的社区基础设施加剧。对重金属的生理反应 包括铅，镉和铜具有复杂的遗传结构，并且已知几种重金属 阻碍学习和改变行为。但是，这些行为和生理反应对金属压力 通常被孤立地考虑，忽略了金属毒性和 对金属应力的行为反应。我的主要目标是剖析和表征整个生物 重金属反应通过采用综合方法来检查遗传基础 生理，行为和进化反应对重金属应激。精英遗传模型果蝇 Melanogaster是我研究的理想选择，因为它与人类共享许多重金属响应基因，这是 非常容易进行大规模的表型测定法，以及大量复杂的工具 可用于促进深入的行为和基因组实验。我将铜视为我的型号重金属 因为，尽管正常发育和生理功能在低水平上需要，但它是一个常见的 重金属污染物由也与铅，锰相互作用的基因代谢和生物蓄积 锌和镉。使用AIM 1，我将解开生理和行为之间的遗传联系 使用大型遗传稳定菌株和大规模结合的大量映射面板对铜应力的响应 多个行为特征的筛选，具有在多个生命阶段收集的生理数据。与AIM 2一起 将表征对铜选择的遗传和协同进化反应。 高和低铜的自然种群。 AIM 2将涉及进化和重新陈述（E＆R） 接近散装RNA条形码和测序（BRB-seq）以跟踪等位基因的动态变化 频率和基因表达通过人工选择的铜电阻过程。调查 当我们寻求的过程中，导致复杂性状变化的进化过程具有极大的生物医学意义。 了解有助于有助于 人群中对有毒重金属暴露的敏感性增加。这种综合方法利用 QTL映射，整个基因组和RNA-seq，可用于D的复杂功能验证工具。 Melanogaster模型系统和实验进化。这项工作最终将允许表征 化学感应能力的遗传变异，与决策做出有关的特征以及神经功能 在多种合成和自然衍生的遗传背景中对铜应激的反应。在一起，这些 方法将为多个响应特征的相互联系提供批判性的见解，同时也 照明影响与金属中毒有关的行为和学习障碍的遗传因素。