Comparative Genomics of Non-Coding Regions to Facilitate Translational Research

描述（由申请人提供）：越来越多的证据表明，调节基因表达的非编码序列的变异在人类疾病中起着重要作用。然而，由于我们无法确定哪些变异存在于基因调控序列中，导致疾病的非编码、调控多态性的鉴定受到限制。最近的多项研究表明，通过比较序列分析鉴定出的高度保守的非编码区往往具有基因调控活性。因此，序列保护本身可以优先考虑基因调控功能的非编码序列。虽然预期高度保守的非编码区域的变异更有可能是有害的是合理的，但很少有研究直接在临床人群中验证这一假设。因此，本提案的目标是研究比较基因组学在几种疾病模型中对功能性非编码序列变异进行优先排序的效用，并建立使临床研究人员能够使用该策略的计算资源。为了实现这一点，我们将首先根据一系列比较基因组标准对非编码序列变异进行分类，以估计其有害的可能性。与i2b2临床研究人员的合作将使我们能够在哮喘的临床研究中测试这种分类的有效性。在VISTA成功的基础上，我们的比较基因组工具套件已经被生物医学界广泛使用，我们将开发一个用户友好的“临床比较基因组门户”来自动化这一过程。最后，将门户网站集成到i2b2的Hive架构和临床研究图表中，将使临床研究人员能够在分析i2b2丰富的临床数据库时利用计算和基于临床序列的数据的协同作用，并加速将临床遗传数据转化为功能见解。为了促进比较门户网站的传播和采用，我们将与i2b2协调，专门针对临床用户举办线上和线下培训活动。公共卫生相关性：由于基因组科学和测序技术的进步，在不久的将来，对人类常见疾病的遗传研究将变得越来越频繁。常见疾病，如糖尿病和心血管疾病，是人类发病和死亡的主要原因。需要新的计算方法来帮助将这些研究中获得的遗传信息转化为可用于了解疾病机制和开发新的诊断和治疗方法的功能信息。在本提案中，我们将利用我们在比较序列分析方面的专业知识开发一个计算平台，以帮助整合基于人类基因组序列的计算和临床数据，并加速将遗传发现转化为功能和医学见解。该平台将通过美国国立卫生研究院支持的i2b2临床研究图表广泛提供给临床研究人员。

DESCRIPTION (provided by applicant): There is increasing evidence that variations in non-coding sequences that regulate gene expression play an important role in human disease. However, the identification of non-coding, regulatory polymorphisms contributing to disease is limited by our inability to identify which variants reside within gene regulatory sequences. Multiple recent studies indicate that highly conserved non-coding regions identified by comparative sequence analysis often possess gene regulatory activity. Thus, sequence conservation alone can prioritize noncoding sequences for gene regulatory function. While it is reasonable to expect that variations in highly conserved non-coding regions are more likely to be deleterious, very little research has been directed to validate this hypothesis in clinical populations. Accordingly, the goal of this proposal is to investigate the utility of comparative genomics for the prioritization of functional non-coding sequence variations in several disease models and to build computational resources enabling the employment of this strategy by clinical investigators. To accomplish this, we will first classify non- coding sequence variations based on a range of comparative genomic criteria to estimate their likelihood of deleteriousness. Collaboration with i2b2 clinical investigators will enable us to test the validity of this classification in a clinical study of asthma. Building on the success of VISTA, our suite of comparative genomic tools already widely used by the biomedical community, we will develop a user-friendly "clinical comparative genome portal" to automate this process. Finally, integration of the portal into i2b2's Hive architecture and clinical research chart will enable clinical investigators to exploit the synergies of computational and clinical sequence-based data in their analysis of i2b2 rich clinical databases and to accelerate the translation of clinical genetic data into functional insights. To facilitate the dissemination and adoption of the comparative portal, in coordination with i2b2 we will organize online and offline training activities specifically targeted at clinical users. PUBLIC HEALTH REVELANCE: Genetic studies of common human diseases will become increasingly frequent in the near future, thanks to advances in genomic science and sequencing technologies. Common diseases, such as diabetes and cardiovascular disease, are among the major causes of human morbidity and mortality. Novel computational approaches are needed to help translate the genetic information obtained in such studies into functional information that can be used to understand the mechanisms of disease and develop new diagnostic and therapeutic approaches. In this proposal, we will use our expertise with comparative sequence analysis to develop a computational platform to help integrate computational and clinical data based on the sequence of the human genome and accelerate the translation of genetic findings into functional and medical insights. This platform will be widely available to clinical investigators through the NIH-supported i2b2 clinical research chart.