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

项目描述（申请人提供）：我们计划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，重点研究晶状体和视网膜相关疾病。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，可以极大地促进对全基因组关联研究（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，我们将使用可用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，以搜索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，并开发一个使用DNA元件百科全书（ENCODE）项目中可用的表观基因组数据的变异优先级框架。在Aim 4中，我们建议使用我们已经开发的定制工作流系统，将我们发现的变体与眼病特定变体数据库和探索平台中现有资源的信息集成在一起。许多提出的分析利用了最初为癌症基因组分析而开发的工具。基因调控网络、改进的算法和集成的工作流程在本提案中开发，可能是一个广泛适用于眼科研究界的资源。

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.