Evolutionary Dynamics of Post-translational Regulatory Networks

描述（由申请人提供）：由复制事件、重组和点突变产生的遗传变异是物种进化过程中自然选择的原材料。为了充分了解生物系统，我们必须了解进化过程，以及这种变异是如何转化为对适合度有可测量影响的表型变化的。基因组研究，特别是比较基因组学，对于研究基因组进化，识别功能性DNA元素，以及引导我们建立更复杂的转录基因调控模型至关重要。最近，质谱技术的进步揭示了转录后调控的复杂世界，并挑战了我们目前对信号系统的看法。现在，每项研究都常规地鉴定出数千种不同的翻译后修饰（PTM）位点，并且不同类型的丰富PTM的列表正在增长（例如磷酸化，乙酰化，泛素化，聚合化等）。这些技术发展提出了功能表征的问题，这是本提案旨在解决的问题。加州大学旧金山分校为开展这项研究提供了一个理想的环境，充满活力和协作精神，并拥有优秀的质谱设备，其中包括上一代质谱仪器。自从来到UCSF，在HFSP奖学金的支持下，我与该机构合作进行了蛋白质磷酸化的跨物种质谱研究。这项初步研究表明，在进化过程中，蛋白质磷酸化的调节可能会迅速分化，尽管尚不清楚这些变化在多大程度上具有功能后果。这项工作强调了跨物种研究的重要性，以及开发蛋白质调节网络的正式模型的迫切需要。我们应该利用基因组研究的经验教训，并将其应用于转录后调控网络的研究。考虑到这一点，本提案的主要目标是：1)使用比较蛋白质组学方法来编目和识别功能重要的ptm；2)开发能够根据ptm功能对其进行分类的预测因子；3)建立不同物种的这些调控网络模型。除了提高我们对信号传导和细胞相互作用网络进化动力学的理解外，从这些模式生物中吸取的经验教训将应用于人类遗传变异的研究。

DESCRIPTION (provided by applicant): Genetic variation, created by duplication events recombination and point mutations serves as the raw material for natural selection to act upon during the evolution of species. To fully understand biological systems we must understand the evolutionary process and how this variation is translated into changes in phenotypes that have a measurable impact on fitness. Genome research and comparative genomics in particular have been crucial to study genome evolution, to identify functional DNA elements and has led us to ever more sophisticated models of transcriptional gene regulation. More recently, progress in mass-spectrometry is unveiling a complex world of post-transcriptional regulation and is challenging our current view of signaling systems. Thousands of different post-translational modification (PTM) sites are now routinely identified per study and the list of different types of abundant PTMs is growing (e.g. phosphorylation, acetylation, ubiquitylation, sumoylation, etc). These technological developments raise a problem of functional characterization, an issue this proposal aims to address. UCSF provides an ideal environment to conduct this research with a vibrant and collaborative spirit and an excellent Mass-Spectrometry facility containing last-generation MS instrumentation. Since arriving at UCSF, with the support of a HFSP fellowship, I have collaborated with this facility to perform a cross-species MS study of protein phosphorylation. This initial study revealed that the regulation by protein phosphorylation can diverge quickly during evolution although it is not yet clear to what extent these changes have a functional consequence. This work underscores the importance of cross-species studies and the crucial need to develop formal models of protein regulatory networks. We should make use of the lessons learned from genome research and applied them to the study of post- transcriptional regulatory networks. With this in mind, the main objectives of this proposal are to 1) use a comparative proteomics approach to catalog and identify functionally important PTMs; 2) to develop predictors that can classify PTMs according to their function and 3) create models of these regulatory networks for different species. Besides improving our understanding signaling and of the evolutionary dynamics of cellular interaction networks, lessons learned from these model organisms will then be applied to the study of human genetic variation. PUBLIC HEALTH RELEVANCE: Understanding the evolutionary process is a fundamental problem in biological research. This project focuses specifically on the study of if the important post-transcriptional regulatory networks that regulate protein function inside the cell. These networks will be compared across different fungi allowing us for the first time to understand how these networks change during evolution. Studying how changes at the level of DNA result in a phenotypic difference with impact on fitness will help us understand why some specific mutations result in disease and why different species react differently to different drugs or environmental conditions.