Systems Biology of Protein and Phenotypic Evolution

项目摘要/摘要 进化系统生物学中一个目前尚未解决的重要挑战是 描述不同层次的生物组织之间的机制和相互作用 塑造蛋白质、细胞网络和表型的进化。我们的实验室已经 对了解进化、系统和细胞生物学之间的相互关系感兴趣 已经十多年了。我们之前已经进行了计算和实验分析 探索多层次组织的演变过程。在本提案中，我们将 在蛋白质、网络、细胞和表型尺度上整合约束和影响，以 开发一个描述蛋白质进化的综合和量化框架。我们将使用 用计算-实验相结合的方法来探索这样的基本科学问题 AS：全球蛋白质适合度格局如何影响蛋白质的短期和长期模式 进化论？细胞网络的结构和功能如何影响蛋白质进化 改变？细胞类型和组织特异性限制在蛋白质进化中的作用是什么？多么 蛋白质谱系的进化是否会影响观察到的表型模式和比率 进化论？因为生物系统不仅约束，而且本身也是产品 关于进化论，探索上述主题也将使我们能够解决重要的生物学问题 问题。例如，蛋白质表达水平和效率如何以及在多大程度上 蛋白质功能在进化中被优化，以及细胞网络的变化可能如何驱动 微生物表型进化。除了了解基本的生物学问题外， 提案结果将对生物医学产生重要影响。具体来说，他们将允许 更好地理解和预测基因突变对蛋白质功能的定量影响， 细胞网络，不同的细胞类型和发育阶段，并最终对物种的 表型。

Project Summary/Abstract An important and currently unsolved challenge in evolutionary systems biology is to describe how the mechanisms and interactions between different levels of biological organization shape the evolution of proteins, cellular networks, and phenotypes. Our laboratory has been interested in understanding the inter-relationships between evolution and systems and cell biology for more than a decade. We have previously carried out computational and experimental analyses exploring evolutionary processes at multiple levels of organization. In this proposal we will integrate constraints and effects at the protein, network, cellular, and phenotypic scales, towards developing an integrated and quantitative framework describing protein evolution. We will use a combined computational-experimental approach to pursue such fundamental scientific questions as: How do global protein fitness landscapes affect short- and long-term patterns of protein evolution? How do the structure and function of cellular networks affect protein evolutionary changes? What is the role of cell type- and tissue-specific constraints on protein evolution? How does the evolution of protein repertoires influence the observed patterns and rates of phenotypic evolution? Because biological systems not only constrain, but are also themselves the products of evolution, exploring the aforementioned topics will also allow us to address important biological questions. For example, how and to what extent protein expression levels and the efficiency of protein function are optimized in evolution, and how changes in cellular networks may drive microbial phenotypic evolution. In addition to understanding fundamental biological questions, proposal results will have important implications for biomedicine. Specifically, they will allow to better understand and predict the quantitative effects of genetic mutations on protein function, cellular networks, diverse cell types and developmental stages, and ultimately on species’ phenotypes.