Bioinformatics Analysis of DNA Alterations in Transcription Factor Binding Sites

从相同的DNA序列，身体能够产生各种细胞，如大脑或肌肉。细胞类型之间的差异取决于每种细胞中哪些基因是活跃的。细胞包含数十万个分散在DNA中的调控区域，每个基因都由一个或多个这些区域控制。一个基因的活性是由蛋白质调节的，这些蛋白质被称为转录因子，它们识别基因的调节区域，并与这些区域的特定DNA序列结合。最近的方法和技术进步的实验程序允许识别的确切位置在DNA中的转录因子结合。然而，仍然不可能对所有> 1，500个转录因子进行这种类型的测定。研究项目和预期结果 * 描述转录因子与DNA结合的位置是理解它们调节哪些基因的基础。在过去的十年中，已经设计了许多计算方法来解决这个问题。然而，预测DNA中转录因子的结合位置仍然是一个持续的挑战。最近的一次竞赛反映了这一点，该竞赛旨在确定为此目的的最佳执行方法，并汇集了来自地球仪的科学家。在这个项目中，我建议提高转录因子结合位置的预测。这将通过以下方式实现：**1）开发创新模型，解释转录因子如何基于多种特征与DNA结合，例如DNA的形状，DNA片段的可访问性，DNA序列在物种间的保守程度;*2）更新我们目前的软件和数据库，以预测这些新模型的转录因子结合位置。所开发的软件和工具将在网上免费提供，供研究界使用。* *该项目将开发的工具和数据将使研究任何类型生物的研究人员受益;*2）随着确定DNA序列的成本迅速下降，与基因调控相关的数据将以前所未有的速度生成。为了分析这些数据，研究人员将需要改进的算法和方法，例如将在本项目中开发的软件和工具类型;*3）通过本项目，我将培养基因组学和生物信息学方面的高素质人才。该实验室有一个模范的记录，其成功的职业生涯对加拿大有积极的影响。

BACKGROUND****From the same DNA sequence, the body is able to generate a wide range of cells, such as brain or muscle. The differences between cell types are determined by which genes are active in each of them. Cells contain hundreds of thousands of regulatory regions scattered across DNA, and each gene is controlled by one or more of these regions. A gene's activity is regulated by proteinsknown as transcription factorsthat recognize the gene's regulatory regions and bind to specific DNA sequences at these locations. Recent methodological and technological advances in experimental procedures allow for the identification of the exact locations in DNA where transcription factors bind. However, it is still not possible to perform this type of assay for all >1,500 transcription factors.******RESEARCH PROJECT AND ANTICIPATED OUTCOME***Delineating the locations where transcription factors bind to DNA is fundamental towards understanding which genes they regulate. In the past decade, many computational methods have been devised to tackle this problem. However, predicting the binding locations of transcription factors in DNA is still an ongoing challenge. This is reflected by a recent competition aimed to identify the best performing method for such purpose, and that brought together scientists from all around the globe. In this project, I propose to improve the prediction of transcription factor binding locations. This will be accomplished by:******1) developing innovative models that explain how transcription factors bind to DNA based on multiple features, such as the shape of DNA, how accessible a segment of DNA is, how well conserved the DNA sequence is across species; and***2) updating our current software and databases for the prediction of transcription factor binding locations with these new models.******The developed software and tools will be freely available online for use by the research community.*******BENEFITS***Expected benefits to Canada and to the worldwide research community include:******1) Due to their similar mechanisms, the regulatory regions that control the activity of genes and the transcription factors that recognize and bind to them are studied from bacteria to primates. The tools and data that will be developed in this project will benefit researchers working with any kind of organism;***2) With the costs of determining the sequence of DNA dropping rapidly, data related to the regulation of genes will be generated at unprecedented rates. To analyze these data, researchers will require improved algorithms and methods, such as the types of software and tools that will be developed in this project; and***3) Through this project, I will train highly qualified personnel in genomics and bioinformatics. The lab has an exemplary record of trainees whose successful careers have a positive impact on Canada.*****