Developmental Mechanisms of Trachea-Esophageal Birth Defects

综合基因组学核心的目标是提供一个全面、成本效益高和高度集成的管道，以分析和相互关联所有项目的基因组数据，并加快计划的实施。该计划项目的所有组成部分都依赖于基因组分析。Project-1将对患者-父母三人组进行完整的外显子组测序(WES)，以确定可能导致TED的突变。Project-2和Project-3将在动物模型和hPSC衍生的TE有机化合物中确定HH、BMP、Gli2/3和Sox2的转录靶标，并确定这些途径如何在基因调控网络(GRN)中相互作用。通过将这些项目中每个项目的基因组数据与来自不同功能基因组数据库的信息相结合，我们将注释项目-1中的候选患者变体，并对那些在项目-2和项目-3中测试的变量进行优先排序。最后，我们将对导致TED的突变进行建模，以确定它们如何扰乱管理TE发展的GRN。总而言之，这将提供对TED的基因-表型基础的系统水平的理解。因此，每个项目以及它们之间的有效信息流，都需要综合基因组学核心提供的严格的计算、统计和信息学分析。我们汇集了来自哥伦比亚大学和CCHMC的基因组学和计算专家团队，以创建一个核心，具有这两个机构都不容易获得的协同专业知识套件。这为整个计划提供了具有成本效益的、最先进的支持，并促进了项目之间的协同，从而提高了生产率并加速了总体目标。核心由哥伦比亚基因组中心副主任沈博士和CCHMC的Zorn博士共同指导，前者是研究人类疾病遗传学的计算基因组学方法的专家，后者是非洲爪哇模式生物数据库Xenbase的联席主任，他是基因调控网络方面的专家。 核心的目标是： 目的1 WES分析及候选致病变异的鉴定 目的2对动物模型和人PSC衍生的有机物的RNA-SEQ和CHIP-SEQ数据进行分析。 目的3)数据整合以1)阐明GRN控制正常和缺陷TE的发育和2)优先处理候选的TED引起的突变。

The aim of the Integrated Genomics Core is to provide a comprehensive, cost effective and highly integrated pipeline to analyze and inter-relate the genomic data from all of the projects and accelerate the program. All components of this Program Project rely of genomic analyzes. Project-1 will perform whole exome sequencing (WES) of patient-parent trios to identify putative TED-causing mutations. Project-2 and project-3 will identify the transcriptional targets of HH, BMP, Gli2/3 and Sox2 in animal models and hPSC-derived TE organoids and determine how these pathways interact in a gene regulatory network (GRN). By integrating genomic data from each of these projects with information from diverse functional genomic databases, we will annotate candidate patient variants from project-1, prioritizing those to test in projects-2 and -3. Finally we will model the TED­causing mutations to determine how they disrupt the GRN governing TE development. Together this will provide a systems level understanding of genotype-phenotype basis of TEDs. Thus, each of the projects, and the effective information flow between them, requires the rigorous computational, statistical and informatics analyses provided by the Integrated Genomics Core. We have assembled a team of genomics and computational specialists from Columbia and CCHMC to create a core with a synergistic suite of expertise not readily available at either institution. This provides cost effective, state-of-the-art, support for the entire program and facilitates synergy between the projects thus enhancing productivity and accelerating the overall goals. The core is jointly directed by Dr. Shen the Associate Director of the Columbia Genome Center, an expert computational genomics methods to study the genetics of human diseases, and Dr. Zorn at CCHMC, the co-Director of Xenbase, the Xenopus model organism database, who is an expert in gene regulatory networks. The aims of the core are: Aim 1 Analysis of WES and identification of candidate disease causing variants Aim 2 Analysis of RNA-seq and ChIP-seq data from animal models and human PSC-derived organoids. Aim 3 Data integrations to 1) elucidate GRN controlling normal and defective TE development and 2) prioritize candidate TED-causing mutations.