Linking sequence and copy number variation to eye diseases by regulatory genomics

描述(由申请人提供)：我们建议开发和应用创新的生物信息学分析工具来研究视力障碍的基因组学，重点是与晶状体和视网膜相关的疾病。我们假设，对现有功能基因组数据集的综合分析，如基因表达谱、组蛋白修饰、转录因子结合和扰动实验，可以极大地促进在全基因组关联研究(GWAS)或全基因组/外显子组测序研究中发现的序列和拷贝数变异的解释。在目标1中，我们将使用现有的基因组数据集来构建晶状体和视网膜的基因调控网络。在目标2中，我们将使用改进的跨平台分析方法，对Gwas数据集进行荟萃分析，以寻找与表型相关的拷贝数变异。在目标3中，我们将开发外显子组数据的拷贝数变异检测算法，并利用可从DNA元件百科全书(ENCODE)项目获得的表观基因组数据开发一个变体优先排序的框架。在目标4中，我们建议使用我们已经开发的定制工作流系统，将我们找到的变体与现有资源中的信息整合到眼病特定变体数据库和探索平台中。许多拟议的分析都利用了最初为癌症基因组分析开发的工具。在这项提案中开发的基因调控网络、改进的算法和集成的工作流程很可能成为眼科研究社区广泛适用的资源。

DESCRIPTION (provided by applicant): We propose to develop and apply innovative bioinformatic analysis tools for studying the genomics of vision disorders, focusing on lens- and retina-related diseases. We hypothesize that integrative analysis of existing functional genomic datasets, such as profiles of gene expression, histone modification, transcription factor binding, and perturbation experiments, can greatly facilitate interpretation of sequence and copy number variants identified in genome-wide association studies (GWAS) or whole-genome/exome sequencing studies. In Aim 1, we will use available genomic datasets to construct a gene regulatory network for both the lens and the retina. In Aim 2, we will perform meta-analysis of GWAS datasets to search for copy number variants that are correlated with the phenotype, using improved methods for cross-platform analysis. In Aim 3, we will develop copy number variation detection algorithm for exome data and develop a framework for prioritization of variants using epigenomic data available from the Encyclopedia of DNA Elements (ENCODE) project. In Aim 4, we propose to integrate the variants we find with information from existing resources in an eye-disease specific variant database and exploration platform, using a customized workflow system we have already developed. Many of the proposed analyses take advantage of the tools that were developed originally for cancer genome analysis. The gene regulatory networks, improved algorithms, and integrated workflows developed in this proposal are likely to be a widely applicable resource to the eye research community.