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

联系PD/PI：艾弗曼，伊丽莎白 项目总结 重金属污染具有广泛的环境、健康和进化影响。在人类中，健康风险 从永久性神经疾病到退行性综合征发病率增加的各种重金属 贫穷和脆弱的社区基础设施加剧了这些问题。对重金属的生理反应 包括铅、镉和铜在内，都有复杂的遗传结构，而且已知有几种重金属。 妨碍学习和改变行为。然而，这些对金属应激的行为和生理反应 通常被孤立地考虑，忽视了金属毒性和 对金属应激的行为反应。我的主要目标是剖析和描述整个生物体 通过采取综合的方法来考察重金属反应与遗传基础之间的关系 对重金属胁迫的生理、行为和进化反应。果蝇的精英遗传模型 黑腹黑素是我研究的理想选择，因为它与人类有许多共同的重金属反应基因。 非常容易进行大规模的表型分析，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。我把铜当作我的典范重金属 因为，尽管正常发育和生理功能所需的水平较低，但它是一种常见的 由基因代谢和生物积累的重金属污染物，这些基因还与铅、锰、 锌和镉。在目标1中，我将解开生理和行为之间的遗传联系 利用遗传稳定菌株的大作图小组和结合大规模的组合对铜胁迫的响应 筛选多种行为特征，并收集多个生命阶段的生理数据。在目标2中，我 将表征多个群体中对铜选择的遗传和共同进化反应，这些群体来自 耐铜性高、低的自然种群。目标2将涉及进化和重新排序(E&R) 结合批量RNA条码和测序的方法(BRB-SEQ)跟踪等位基因的动态变化 通过对铜抗性的人工选择过程中的频率和基因表达。调查 导致复杂性状变异的进化过程具有重大的生物医学意义 了解基因与环境的相互作用、遗传约束和遗传风险因素 人类对有毒重金属暴露的易感性增加。这种综合方法充分利用了 QTL作图、全基因组和RNA-seq、可用于D. 黑猩猩模型系统，以及实验进化。这项工作最终将允许描述 化学感觉能力、与决策相关的性状和神经功能的遗传变异 在不同的人工合成和自然衍生的遗传背景下对铜胁迫的反应。加在一起，这些 方法将提供对多种反应特征的相互联系的关键洞察，同时还 阐明与金属中毒有关的影响行为和学习障碍的遗传因素。

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.