Evolution-guided Studies of Mitochondrial Functions

项目摘要 虽然基因组学已经导致了一组广泛的预测基因， 仍然是限速的。为了推动基因功能的发现，我们利用宿主-病毒界面和 冲突除了揭示宿主的防御机制外，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器（例如SRC，P53）的定义。这里我们 利用我们的综合框架-称为病毒-发现和表征新的主机- 病毒接口。具体来说，我们使用与感染结果相关的因素所特有的冲突基因组疤痕， 结合基于细胞的和病毒感染的测定鉴定未表征的基因。我们策略的优点是 这通过脊椎动物特异性肌间应激反应（MISTR）回路的识别来说明。MISTR 由相关的电子传递链因子执行，并由 压力信号，如感染和缺氧。使用VIRONATIONAL框架，该研究计划正在定义 线粒体中的新战线被数百种病毒编码因子所突出，这些因子可能针对这个细胞器 来驱动病毒复制。由于我们的多维生物信息学屏幕作为肥沃的土壤， 识别宿主防御和发现教科书功能的新维度，我们正在开发病毒作为一种 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， 病毒性水泡性口炎病毒（VSV）是一种模式RNA病毒，沿着广泛的分子工具包， 我们将缩小缺乏功能的基因的差距。总的来说，我们的创新框架继续 利用病毒系统通过利用经典的进化论和生物学方法的组合来推动生物学发现的丰富历史 和分子特征与实验分析配对以表征机制。 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