Snake venom systems as a model for inferring the structure and evolution of regulatory networks underlying organism-level physiological traits

蛇毒系统作为推断生物体水平生理特征调控网络的结构和进化的模型

• 批准号: 2307044
• 负责人: Todd Castoe
• 金额: $ 150.14万
• 依托单位: University of Texas at Arlington
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2307044&HistoricalAwards=false
• 关键词: Snake; venom; systems; model; inferring

How new traits arise, how organism-level phenotypes manifest through variation at the cellular level, and how trait variation is impacted by genomic changes that modify gene regulatory networks are fundamental questions for understanding the genomic basis of organismal phenotype. This collaborative project links these topics through studies of snake venom systems and the genomic, regulatory, physiological, cellular, and evolutionary mechanisms that drive variation in venom composition. The research aims to transform current understanding of gene regulatory mechanisms by integrating inferences across scales of biological organization, from single cells to whole organisms, and from within populations to distantly related species, and by applying new predictive frameworks to link genetic and phenotypic variation. New statistical approaches that leverage both cellular and evolutionary variation to generate, test, and refine hypotheses for how gene regulatory networks function – innovations that are broadly applicable to any eukaryotic system – will be developed and disseminated. The research will advance fundamental understanding of how natural selection acts to evolve, maintain, and finely tune complex traits. Mentoring and research training in integrative biology will be provided for 22 undergraduate and 8 graduate students across four institutions, and a course-based undergraduate research experience (CURE) will be implemented. In addition, the project includes workshops and online modules to enhance training in state-of-the-art genomics and biological data science. By providing new insights into how snake venom variation is regulated, the project will have broad ramifications for improving global treatment of snakebite, with potential to impact millions globally.The overarching goal of this research program is to advance the ability to understand and predict how new gene regulatory networks arise and how variation in these networks shape complex physiological traits, using snake venom as a model system. This research aims to understand how complex physiological traits are controlled, how these regulatory networks arise and subsequently re-wire existing physiological systems, and to identify the mechanisms that shape cellular and evolutionary variation in organismal phenotypes. This project will formulate, refine, and test mechanistic hypotheses for gene regulatory networks underlying venom composition by integrating across biological and evolutionary scales, and by leveraging emerging statistical frameworks to link genomic variation and gene regulatory variation with cellular and evolutionary trait variation. New methods developed will integrate predictive approaches and diverse functional genomic data to test mechanistic hypotheses and predict the roles of regulatory elements, trans-acting factors and other features that govern venom composition, and to test how cellular and evolutionary heterogeneity together shape organismal-level phenotypes. Key products of this work include novel approaches and software that leverage both single-cell variation and evolutionary variation to explicitly test hypotheses for the roles of gene regulatory components (e.g., cis-regulatory elements and trans-regulatory factors) that will be broadly applicable for developing and testing hypotheses for gene regulatory mechanisms in any eukaryotic system. The proposed research includes methodological and theoretical scientific innovation, development of new tools and software for understanding and testing hypotheses of regulatory networks and their evolution, training, establishment of collaborative networks, and impactful outreach.This project is jointly funded by BIO-IOS-Physiological Mechanisms and Biomechanics, BIO-DEB-Evolutionary Processes, and BIO-DEB-Systematics and Biodiversity Science.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

新特征如何出现，生物水平的表型如何通过细胞水平的变异表现出来，以及特征变异如何受到基因组变化的影响，基因组变化改变了基因调节网络是理解有机表型基因组基础的基本问题。该协作项目通过研究蛇毒系统的研究以及驱动毒液组成变化的基因组，调节，物理，细胞和进化机制将这些主题联系起来。该研究旨在通过整合从单个细胞到整个组织，从种群到明显相关的物种，以及应用新的预测框架以将遗传和表型变异联系起来，从而改变当前对基因调节机制的理解。利用细胞和进化变化的新统计方法来生成，测试和完善有关基因调节网络功能的假设 - 将开发和传播的基因调节网络功能 - 广泛适用于任何真核系统的创新。这项研究将促进对自然选择如何发展，维持和细微调整复杂性状的基本理解。将为四个机构的22名本科生和8名研究生提供综合生物学的指导和研究培训，并将实施基于课程的本科研究经验（CURE）。此外，该项目还包括研讨会和在线模块，以增强最先进的基因组学和生物数据科学的培训。通过提供有关如何调节蛇毒液变异的新见解，该项目将在改善蛇咬的全球治疗方面产生广泛的影响，并有可能影响数百万人在全球范围内影响数百万人。该研究计划的总体目标是提高和预测这些网络的新基因调节网络以及如何使用这些网络的生理特征，并如何使用Snekemotic Traits，并如何使用Snece Complical Traits，并如何使用模型系统。这项研究旨在了解如何控制复杂的生理特征，如何控制这些调节网络并随后重新连接现有的物理系统，并确定塑造有机表型中细胞和进化变化的机制。该项目将通过在生物学和进化量表之间整合毒液组成的基因调节网络，并利用新兴统计框架将基因组变异和基因调节性变异与细胞和进化性状变异联系起来，以制定，完善和检验机械假设。开发的新方法将整合预测方法和多样化的功能基因组数据，以测试机械假设，并预测控制毒液组成的调节元件，反式作用因子和其他特征的作用，并测试细胞和进化异质性如何塑造有机水平的表型。这项工作的关键产品包括利用单细胞变异和进化变化的新颖方法和软件，以明确测试假设基因调节成分的作用（例如，顺式调节元素和跨调节因素）将广泛地适用于开发和测试基因调节机构中任何e akaryismist in任何eukaryismists in note e ukaryistics in note e eukaryismist in note e ukaryismist in note note。 The proposed research includes Methodological and theoretical scientific innovation, development of new tools and software for understanding and testing hypotheses of regulatory networks and their evolution, training, establishment of collaborative networks, and impactful outreach.This project is jointly funded by BIO-IOS-Physiological Mechanisms and Biomechanics, BIO-DEB-Evolutionary Processes, and BIO-DEB-Systematics and Biodiversity Science。该奖项反映了NSF的法定任务，并通过使用基金会的知识分子优点和更广泛的影响审查标准评估来诚实地支持支持。