A TOOLKIT FOR IDENTIFYING CAUSAL VARIANTS IN TRANSCRIPTIONAL ENHANCERS

描述（由申请人提供）：我们的长期目标是了解增强子序列变化影响基因表达的机制。全基因组关联研究（GWAS）和表达数量性状位点（eQTL）定位揭示了数千种与常见疾病和基因表达变异相关的序列变异。很大一部分相关变异位于远离基因的地方，这使得它们难以解释。鉴于其丰富程度和在基因调控中的重要作用，转录增强子的序列变异可能是许多表型变异的原因。目前，识别这些变异仍然是一个挑战，因为有几个障碍：1)组织特异性增强子的基本注释；ii)缺乏精确确定增强子内转录因子结合位点（TFBSs）的身份和位置的策略；缺乏分配增强子目标的策略。通过解决这些障碍，该项目的目标是设计和测试一个计算框架，使系统和快速筛选导致复杂疾病的增强子序列变异成为可能。作为我们方法的最终测试，我们将应用我们的计算策略来筛选和表征与一种常见的自身免疫性疾病——1型糖尿病相关的增强子变体。为了使本项目中开发的方法对更广泛的用户社区有用，我们将开发一个开源软件套件和一个数据库，专门用于分析和管理增强子中的调节突变。预计该项目的成果将产生重大影响

DESCRIPTION (provided by applicant): Our long-term goal is to understand the mechanisms by which sequence variations in enhancers affect gene expression. Genome-wide association study (GWAS) and expression quantitative trait loci (eQTL) mapping have revealed thousands of sequence variants that are associated with common diseases and gene expression variations. A large portion of the associated variants is located far away from genes, making them difficult to interpret. Given its abundance and essential role in gene regulation, sequence variants in transcriptional enhancers could be the cause of many phenotypic variations. Currently, identifying such variants remains a challenge because of several hurdles: i) rudimentary annotation of tissue-specific enhancers; ii) lack of strategies to precisely pinpoint the identity and location of transcription factor binding sites (TFBSs) within an enhancer; and iii lack of strategies to assign enhancer targets. By addressing these hurdles, the objective of this project is to design and test a computational framework that enables systematic and rapid screen of enhancer sequence variants that cause complex diseases. As an ultimate test of our approach, we will apply our computational strategy to screen and characterize enhancer variants that are associated with a common autoimmune disease, Type 1 Diabetes. To make the methods developed in this project useful to a much broader community of users, we will develop an open-source software suite and a database dedicated to the analysis and curation of regulatory mutations in enhancers. It is anticipated that the outcomes of this project will have an important positive impact because it promises to significantly accelerate the discovery and systematic documentation of causal genetic variants in the noncoding portion of the human genome.