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

每个个体的基因组产生大量的细胞表型，这取决于哪些基因被表达。因此，基因表达是将基因型转化为表型的重要步骤。基因表达的调节是对环境的反应，允许表型的变化，可以帮助生物体适应各种生活条件。迄今为止，大多数关于影响基因表达的遗传变异的研究都是在单一环境中进行的，因此很难了解遗传变化如何影响基因调控中依赖环境的方面。该项目将通过研究酵母菌株和品种之间存在的调节网络的差异来填补这一知识空白。在这项工作的过程中，实验和计算的进步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，一个博物馆展览也将被开发出来，这将有助于向公众宣传进化生物学的重要性。顺式调控DNA序列或与这些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控变化对物种内部和物种之间表达差异的相对贡献，但这些研究几乎完全集中在同一时间点、同一组条件下的基因表达水平。因此，顺式和反式调控变化对基因表达动态方面的影响，如表达在不同环境或整个细胞周期中如何变化，仍然知之甚少。拟议的项目将通过确定物种内部和物种之间动态基因表达变化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，采用基因组和单基因方法，整合尖端的经验和计算工具，并利用两个研究基因表达超过十年的实验室的互补资源和专业知识。更具体地说，将使用Barkai实验室提供的装置，在各种条件下对Wittkopp实验室中鉴定的一组出芽酵母菌株、物种和杂交种进行分析。数据分析将通过紧密合作进行：Barkai实验室将对数据进行初步处理和质量控制，并建立可用于高通量分析和可视化的数据结构。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，该平台将整合现有基因组学和功能基因组学数据。依靠其在进化理论方面的专业知识，Wittkopp实验室将对数据进行深入的生物学分析，以确定控制网络之间变化的循环原则，并定义具体的预测，以例证这些原则。这两个实验室都将为验证具体预测的后续实验做出贡献。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

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.