Analytic tools to examine high-resolution and genome-scale DNA methylation data

描述（由申请人提供）：DNA甲基化在哺乳动物发育期间调节谱系特化和效力限制中起关键作用;通常在癌症中观察到DNA甲基化的异常模式。亚硫酸氢盐处理的DNA的第二代测序使得能够更详细地检查DNA甲基化，并且最近证明的基于阵列的捕获技术允许在选定的基因组区域中进行超深亚硫酸氢盐测序。该项目开发了基于这些新实验技术的数据制定和测试有关DNA甲基化的特定假设所需的算法和统计方法。将设计一系列统计模型来表征细胞或样品中DNA甲基化的特征，并将设计算法用于模型拟合、概率计算和特征识别的相关计算任务。这些方法将通过应用于新的超深亚硫酸氢盐测序数据进行验证;同时测试有关DNA甲基化调控和甲基化如何调控基因表达的具体假设。将产生与发育和癌症相关的特定甲基化数据集。计算方法将被开发用于识别细胞中甲基化谱的克隆特征，用于预测细胞之间的发育关系，以及用于解决有关肿瘤样品的复杂性和组织学的信息。这些方法的有效和可靠的实施将被开发并发布供公众使用。拟议的研究将提供更高的分析能力，以补充调查DNA甲基化的新兴实验技术。这将使研究人员，特别是那些研究人类发育和癌症的研究人员，能够提出和回答有关DNA甲基化功能的更精确的问题。此外，这项技术将有助于确定与癌症相关的临床结果的最有效的甲基化标记物。 公共卫生相关性：拟议的研究将产生分析技术，以补充分析DNA甲基化模式的新兴实验技术。DNA甲基化参与调节人类发育，异常甲基化模式是癌症基因组的一般特征。通过提高甲基化数据的分析能力，该项目将帮助研究人员阐明DNA甲基化在癌症和发展中的作用和机制。

DESCRIPTION (provided by applicant): DNA methylation plays a critical role in regulating lineage specification and restriction of potency during mammalian development; aberrant patterns of DNA methylation are generally observed in cancers. Second-generation sequencing of bisulfite treated DNA is enabling DNA methylation to be examined in greater detail, and recently demonstrated array-based capture technique allow ultra-deep bisulfite sequencing in selected genomic regions. This project develops algorithmic and statistical methods required to formulate and test specific hypotheses about DNA methylation based on data from these novel experimental technologies. A family of statistical models will be designed to characterize features of DNA methylation in a cell or sample, and algorithms will be designed for associated computational tasks of model fitting, probability calculations and feature identification. The methods will be validated through application to novel, ultra-deep bisulfite sequencing data; specific hypotheses about the regulation of DNA methylation and how methylation regulates gene expression will be tested simultaneously. Specific methylation datasets related to development and cancer will be produced. Computational methods will be developed for identifying clonal features of methylation profiles in cells, for predicting developmental relationships between cells, and for resolving information about the complexity and histology of tumor samples. Efficient and robust implementations of the methods will be developed and released for public use. The proposed research will provide increased analytical capability to complement emerging experimental technology for investigating DNA methylation. This will enable researchers, particularly those studying human development and cancers, to ask and answer more precise questions about the functions of DNA methylation. Moreover, this technology will assist in identifying the most effective methylation-based markers for clinical outcomes associated with cancers. PUBLIC HEALTH RELEVANCE: The proposed research will produce analytic technology to complement emerging experimental technology in analyzing DNA methylation patterns. DNA methylation is involved in regulating human development, and aberrant methylation patterns are a general characteristic of cancer genomes. By providing increased capacity for analyzing methylation data, this project will assist researchers elucidate the role and mechanisms of DNA methylation in cancer and development.