Structural Annotation of the Human Genome

描述：(申请人提供)基因组学方法旨在识别人类基因组中的所有功能成分并了解它们的功能。这种大规模的方法被认为可以极大地提高对人类生物学和疾病的洞察力。在这里，建议进一步开发和验证一种新的和独特的方法来识别人类基因组中的功能元件。该方法基于这样的假设，即序列元件之间的直接物理相互作用将指向它们之间的功能关系。例如，已经证明调控元件与它们的目标基因物理上相互作用来控制转录。基因组元件之间类似的远程相互作用被认为参与了其他基因组过程，如DNA复制、修复、减数分裂重组和染色体凝聚。因此，识别染色体的相互作用和一般的染色体结构特征可能会导致寻找功能元件。这一建议需要进一步开发和验证一种方法，该方法依赖于染色体相互作用的确定和计算分析，作为识别功能元件的一种手段。染色体的相互作用将使用我们开发的一种分子方法--“染色体构象捕捉”或“3C”来测量。这项提案的主要目标是评估使用这一结构方法寻找功能要素的情况。具体目标1：发展强有力的基于3C的战略，以确定人类基因组中的功能元件。具体目标2：为ENCODE项目选定的区域生成两个有重点的互动频率数据集。具体目标3：通过建立结构模型来解释3C相互作用频率数据集。对获得的数据进行分析，并将这些数据与其他ENCODE项目得出的结果相结合，可望提供关于这种染色体结构方法寻找功能元件的适宜性的信息。

DESCRIPTION: (provided by applicant) Genomics approaches aim to identify all functional elements in the human genome and to understand their functions. Such large-scale approaches are thought to greatly increase insights in human biology and disease. Here it is proposed to further develop and validate a new and unique methodology to identify functional elements in the human genome. The approach is based on the hypothesis that direct physical interactions between sequence elements will point to functional relationships between them. For example, regulatory elements have been shown to physically interact with their target genes to control transcription. Similar long-range interactions between genomic elements are thought to be involved in other genomic processes such as DNA replication, repair, meiotic recombination and chromosome condensation. Therefore, identification of chromosomal interactions, and chromosome structural features in general may result in finding functional elements. This proposal entails the further development and validation of an approach that relies on determination and computational analysis of chromosomal interactions as a means to identify functional elements. Chromosomal interactions will be measured using a molecular methodology, "Chromosome Conformation Capture" or "3C" that we have developed. The main goal of this proposal is to assess the use of this structural approach to find functional elements. Specific Aim 1: Development of robust 3C-based strategies to identify functional elements in the human genome. Specific Aim 2: To generate two focused interaction frequency datasets for regions selected by the ENCODE project. Specific Aim 3: To interpret 3C interaction frequency datasets by building structural models. Analysis of the data obtained and integration of these data with results derived from other ENCODE projects is expected to provide information regarding the suitability of this chromosome structural approach to find functional elements.