Bioinformatics Analysis of DNA Alterations in Transcription Factor Binding Sites

背景*从相同的DNA序列中，人体能够产生广泛的细胞，如大脑或肌肉。细胞类型之间的差异是由每种细胞中活跃的基因决定的。细胞包含分布在DNA上的数十万个调控区域，每个基因都由其中的一个或多个区域控制。基因的活性由被称为转录因子的蛋白质调节，这些蛋白质识别基因的调节区，并在这些位置与特定的DNA序列结合。实验过程中最新的方法和技术进步使人们能够确定DNA中转录因子结合的确切位置。然而，仍然不可能对所有的1,500个转录因子进行这种类型的分析。*研究项目和预期结果*描绘转录因子与DNA结合的位置对于了解它们调控哪些基因是基本的。在过去的十年里，已经设计了许多计算方法来解决这个问题。然而，预测转录因子在DNA中的结合位置仍然是一个持续的挑战。最近的一次竞赛就反映了这一点，该竞赛旨在确定实现这一目的的最佳方法，并将来自全球各地的科学家聚集在一起。在这个项目中，我建议改进转录因子结合位置的预测。这将通过以下方式实现：*1)开发创新的模型，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片段的可获得性、DNA序列在不同物种中的保存情况；和*2)使用这些新模型更新我们现有的用于预测转录因子结合位置的软件和数据库。*开发的软件和工具将免费在线供研究社区使用。*对加拿大和世界研究社区的预期好处包括：*1)由于它们的相似机制，控制基因活性的调节区以及识别和结合它们的转录因子从细菌到灵长类动物都得到了研究。这个项目将开发的工具和数据将使从事任何生物体工作的研究人员受益；*2)随着确定DNA序列的成本迅速下降，与基因调控有关的数据将以前所未有的速度产生。为了分析这些数据，研究人员将需要改进的算法和方法，例如将在该项目中开发的软件和工具的类型；以及*3)通过该项目，我将培训基因组学和生物信息学方面的高素质人员。该实验室拥有成功的职业生涯对加拿大产生积极影响的实习生的模范记录。

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.*****