人基因组远程调控元件的疾病表型和功能预测

项目名称： 人基因组远程调控元件的疾病表型和功能预测

项目编号： No.31471245

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 生物科学

项目作者： 田卫东

作者单位： 复旦大学

项目金额： 70万元

中文摘要： 传统上，复杂疾病的研究主要集中在致病基因的鉴定和其分子机制的研究。但基因组中调控元件的序列变异可导致靶基因的转录异常，也可以导致复杂疾病的发生。事实上，大多数与疾病关联的SNP都位于调控元件上，或与其紧密连锁，而其中有很多处于基因间区域，可能与远程调控元件有关。但由于远程调控模式的复杂性，远程调控元件的靶基因很难通过实验鉴定，这导致解释这些SNP的可能致病机制是一个难题。我们在前期的研究工作中开发了一基于染色体构象捕获Hi-C技术的数据和比较基因组数据预测远程调控元件靶基因的方法。在此基础上，本课题计划继续整合其他组学数据来预测远程调控元件的靶基因，并利用预测的靶基因来探索远程调控元件的序列变异与复杂疾病之间的关联，进而建立生物信息学模型来预测远程调控元件的疾病表型及其可能参与调控的生物通路。本课题的研究对于理解远程调控元件的致病机制及其在发育过程中的调控机制具有重要意义。

中文关键词： 生物信息；复杂疾病；基因组；调控网络；计算生物学

英文摘要： Traditionally, the studies of complex disease mainly focus on the identification of disease genes and the study of the molecular mechanism of disease genes. However, sequence variations on regulatory elements in genome may cause alterations in target gene transcription, which may also cause diseases. Current studies have found that majorities of disease-associated SNPs are actually located in or closely linked to regulatory elements, and many of them are located in intergenic regions, indicating they may be associated with distal regulatory elements (DREs). Since the mechanisms of distal regulation are complex, it is challenging to identify the target genes of DREs, making it difficult to explain the causal roles of the intergenic disease-associated SNPs. In our previous studies, we have developed a novel method that combines the data generated by Hi-C technology (a technology that captures chromosome conformation information by high-throughput sequencing) and comparative genomics data to predict the target genes of DREs. Therefore, in this study we aim to use the predicted target genes of DREs to analyze the association of DRE's sequence variation with disease. In addition, we plan to develop bioinformatics models to predict the disease phenotypes of DREs from the predicted target genes. Finally, we plan to extend the models to predict the biological processes in which a DRE may be involved, and classify DREs based on their involved biological processes. Out study will be of importance to the understanding of not only the molecular mechanisms of disease association caused by the sequence variation on DREs, but also the regulatory mechanisms of DREs in cell development.

英文关键词： bioinformatics;complex disease;genome;regulatory network;computational biology