Evolution-guided Studies of Mitochondrial Functions

项目总结 尽管基因组学已经导致了一组广泛的预测基因，但基因产物的功能注释 仍然是限速的。为了推动基因功能的发现，我们利用宿主-病毒接口和签名 冲突。除了揭示宿主防御机制外，对感染细胞和免疫反应的研究还 导致了基本细胞过程和关键主调节因子(例如SRC、P53)的定义。在这里，我们 利用我们的集成框架-称为VIROLOG-来发现和表征新的宿主- 病毒接口。具体地说，我们使用与感染结果相关的因素特有的冲突基因组伤疤来 结合基于细胞的检测和病毒感染检测，识别未鉴定的基因。我们战略的优点是 脊椎动物特异性线粒体应激反应(MISTR)电路的识别就说明了这一点。其他 由相关的电子传输链因子执行，并受由 应激信号，如感染和缺氧。使用VIROLOG框架，该研究计划正在定义 线粒体中的新战线被数百种可能针对该细胞器的病毒编码因子所突显 在感染期间驱动病毒复制。因为我们的多维生物信息屏幕作为肥沃的土壤 识别主机防御并发现教科书功能的新维度，我们正在将VIROLOG开发为 交互式用户数据库和界面。使用“经典”病毒，如牛痘病毒，典型的痘病毒，以及 病毒水泡性口炎病毒(VSV)，一种模型RNA病毒，以及针对关键宿主的广泛的分子工具包 防御，我们将缩小缺乏功能的基因的差距。总的来说，我们的创新框架延续了 通过利用经典进化的组合，使用病毒系统来推动生物发现的丰富历史 分子签名与实验分析相结合，以表征机制。 1

PROJECT SUMMARY Although genomics has led to an expansive set of predicted genes, functional annotation of gene products remains rate-limiting. To drive discovery of gene functions, we exploit host-virus interfaces and signatures of conflict. In addition to revealing host defense mechanisms, studies of infected cells and immune responses have led to the definition of fundamental cellular processes and key master regulators (e.g. SRC, P53). Here, we leverage our integrative framework – termed VIROLOG - for the discovery and characterization of novel host- virus interfaces. Specifically, we use genomic scars of conflict unique to factors linked to infection outcomes to identify uncharacterized genes combined with cell-based and viral infection assays. The merit of our strategy is illustrated by the identification of a vertebrate specific MItochondrial STress Response (MISTR) circuit. MISTR is executed by related electron transport chain factors and regulated by ultraconserved miRNAs induced by stress signals such as infection and hypoxia. Using the VIROLOG framework, this research program is defining new battlefronts in mitochondria highlighted by hundreds of viral-encoded factors that may target this organelle during infection to drive viral replication. As our multidimensional bioinformatic screens serve as fertile ground to identify host defenses and uncover new dimensions to textbook functions, we are developing VIROLOG as an interactive user database and interface. Using “classic” viruses such as vaccinia, the prototypical poxvirus, and virus vesicular stomatitis virus (VSV), a model RNA virus, along with the extensive molecular toolkit for key host defenses, we will narrow the gap of genes lacking function. Collectively, our innovative framework continues the rich history of using viral systems to drive biological discovery by exploiting a combination of classic evolutionary and molecular signatures paired with experimental analysis to characterize mechanisms. 1