NSF/MCB-BSF Evolution of gene expression: from static patterns to dynamic systems

NSF/MCB-BSF 基因表达的演变：从静态模式到动态系统

• 批准号: 1929737
• 负责人: Patricia Wittkopp
• 金额: $ 59.35万
• 依托单位: Regents of the University of Michigan - Ann Arbor
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1929737&HistoricalAwards=false
• 关键词: NSF; MCB; BSF; Evolution; gene

Each individual's genome gives rise to a large array of cellular phenotypes depending on which genes are expressed. Gene expression is thus an essential step in converting genotypes into phenotypes. The regulation of gene expression is responsive to the environment, allowing changes in phenotypes that can help an organism adjust to a variety of living conditions. To date, most studies of genetic variation affecting gene expression have been conducted within a single environment, making it difficult to know how genetic changes affect the environment-dependent aspects of gene regulation. This project will fill this knowledge gap by examining differences in regulatory networks that exist among strains and species of yeast. Experimental and computational advances developed during the course of this work will help other researchers who study gene expression and the evolution of regulatory networks. A museum exhibit will also be developed during the course of this work and will help communicate the importance of evolutionary biology to the general public. Mutations in either cis-regulatory DNA sequences or trans-regulatory factors that interact with these cis-regulatory sequences can alter gene expression. Over the last 15 years, genomic studies of gene expression have investigated the relative contributions of cis- and trans-regulatory changes to expression differences within and between species, but these studies have focused almost exclusively on levels of gene expression assayed at one point in time, under one set of conditions. Consequently, the impact of cis- and trans-regulatory changes on dynamic aspects of gene expression, such as how expression changes in different environments or throughout the cell cycle, remains less understood. The proposed project will fill this knowledge gap by identifying the genetic mechanisms responsible for variation in dynamic gene expression within and between species. To achieve this goal, the researchers will work at multiple evolutionary scales, employ both genomic and single-gene methods, integrate cutting-edge empirical and computational tools, and harness the complementary resources and expertise of two labs that have been studying gene expression for more than a decade. More specifically, a panel of budding yeast strains, species and hybrids characterized in the Wittkopp lab will be profiled under a wide array of conditions using a setup available in the Barkai lab. Data analysis will proceed through tight collaboration: the Barkai lab will perform the initial processing and quality controls of the data, and establish a data structure amendable for high-throughput analysis and visualization. Both labs will then contribute to the establishment of a bioinformatics platform that will integrate the data with existing genomics and functional genomics data. Relying on its expertise in evolutionary theory, the Wittkopp lab will perform in-depth biological analysis of the data to identify recurrent principles governing the variation between networks and define specific predictions exemplifying these principles. Both labs will contribute to follow-up experiments designed to validate specific predictions.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.

每个个体的基因组都会产生大量的细胞表型，这取决于表达的基因。因此，基因表达是将基因类型转化为表型的关键步骤。基因表达的调节对环境做出反应，允许表型发生变化，从而帮助有机体适应各种生活条件。到目前为止，大多数关于遗传变异影响基因表达的研究都是在单一环境中进行的，这使得人们很难知道遗传变化如何影响基因调控的环境相关方面。这个项目将通过检查酵母菌株和物种之间存在的调控网络的差异来填补这一知识空白。在这项工作中开发的实验和计算进展将有助于其他研究基因表达和调控网络进化的研究人员。在这项工作的过程中，还将开发一个博物馆展品，帮助向公众传播进化生物学的重要性。顺式调控DNA序列或与顺式调控序列相互作用的反式调控因子的突变都可以改变基因的表达。在过去的15年里，基因表达的基因组研究已经调查了顺式和反式调节变化对物种内和物种间表达差异的相对贡献，但这些研究几乎完全集中在在一组条件下在某个时间点分析的基因表达水平。因此，顺式和反式调节变化对基因表达的动态方面的影响，如表达如何在不同的环境中或整个细胞周期中变化，仍然知之甚少。拟议的项目将通过确定导致物种内和物种间动态基因表达差异的遗传机制来填补这一知识空白。为了实现这一目标，研究人员将在多个进化尺度上工作，同时使用基因组和单基因方法，整合尖端的经验和计算工具，并利用两个实验室的互补资源和专业知识，这两个实验室已经研究基因表达超过十年。更具体地说，在Wittkopp实验室表征的一组萌芽酵母菌株、物种和杂交种将使用Barkai实验室提供的设置在广泛的条件下进行分析。数据分析将通过紧密合作进行：Barkai实验室将执行数据的初始处理和质量控制，并建立可修改的数据结构，以便进行高通量分析和可视化。然后，这两个实验室将为建立一个生物信息学平台做出贡献，该平台将把数据与现有的基因组学和功能基因组学数据相结合。凭借其在进化论方面的专业知识，Wittkopp实验室将对数据进行深入的生物学分析，以确定支配网络之间变异的反复出现的原则，并定义具体的预测来例证这些原则。这两个实验室都将对旨在验证特定预测的后续实验做出贡献。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。