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

新的性状是如何产生的，生物体水平的表型如何通过细胞水平的变异表现出来，以及改变基因调控网络的基因组变化如何影响性状变异，这些都是理解生物表型的基因组基础的基本问题。这个合作项目通过研究蛇毒系统以及驱动毒液成分变化的基因组、调节、生理、细胞和进化机制来将这些主题联系起来。这项研究的目的是通过整合从单个细胞到整个生物体，从种群内到远亲物种的跨生物组织尺度的推断，并通过应用新的预测框架将遗传和表型变异联系起来，来改变目前对基因调控机制的理解。将开发和传播利用细胞和进化变异来生成、测试和完善基因调控网络如何发挥作用的假说的新的统计学方法--广泛适用于任何真核系统的创新。这项研究将促进人们对自然选择如何进化、维持和微调复杂特征的基本理解。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，并将实施以课程为基础的本科生研究体验(CURE)。此外，该项目还包括讲习班和在线模块，以加强最先进的基因组学和生物数据科学方面的培训。通过对蛇毒变异如何调控提供新的见解，该项目将对改善全球蛇咬伤的治疗产生广泛的影响，有可能影响全球数百万人。该研究计划的总体目标是提高理解和预测新的基因调控网络如何出现，以及这些网络中的变异如何形成复杂的生理特征的能力，使用蛇毒作为模型系统。这项研究旨在了解复杂的生理特征是如何被控制的，这些调控网络是如何产生的，并随后重新连接现有的生理系统，并识别形成生物表型中细胞和进化变异的机制。该项目将通过跨生物和进化尺度的整合，并利用新兴的统计框架将基因组变异和基因调控变异与细胞和进化特征变异联系起来，来制定、完善和测试毒液成分背后的基因调控网络的机制假说。开发的新方法将整合预测方法和不同的功能基因组数据，以测试机械假说和预测调控元件、反式作用因子和其他支配毒液成分的特征的作用，并测试细胞和进化的异质性如何共同塑造有机体水平的表型。这项工作的主要产品包括利用单细胞变异和进化变异来明确测试基因调控成分(例如顺式调控元件和反式调控因子)作用的假说的新方法和软件，这些假说将广泛适用于开发和测试任何真核系统中的基因调控机制假说。拟议的研究包括方法和理论的科学创新，开发新的工具和软件来理解和测试调控网络及其进化的假设，培训，建立协作网络，以及有效的外向。该项目由BIO-IOS-生理机制和生物力学，BIO-DEB-进化过程，BIO-DEB-系统学和生物多样性科学联合资助。该奖项反映了NSF的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。

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.