COMPARATIVE GENOMIC ANALYSIS OF CARDIOVASCULAR GENE REGU

心血管（CV）系统疾病通常是由于时间或 大量但有限的基因表达的定量变化。 非编码顺式调控序列在控制基因中发挥核心作用 表达和物种间（即人/小鼠）基因组序列比较 作为识别此类非编码监管的快速而准确的方法 元素。 该 PGA 的中心目标是使用比较基因组 首先进行识别，然后确定元素的功能 调节影响CV系统的基因表达。 的活动 该 PGA 的重点不是发现新基因，而是利用 比较基因组学以了解顺式调节元件在 CV 研究人员已经在研究基因的表达。在这个 “基因组”探索 CV 基因调控的综合计划，200 人类基因组区间 (=~200 BAC)，每个区间包含一个 CV 基因，将是 比较有特点。 该计划的组成部分将包括：(1) 人类/小鼠和其他哺乳动物基因组直系同源的获取 一组优先 CV 基因的序列。 序列将被访问 来自公共资助的数据库或由测序组件生成 这个PGA。 (2)心血管比较基因组数据库的建立 将包含广泛注释的人类和小鼠序列，包括 保守非编码元件的定位靠近经过深入研究的 CV基因。 (3) 全基因组表达谱发现共同调控的基因 与 CV 基因并识别共享的非编码调控元件，通过 种内分析。 (4) 保守非内 SNP 的鉴定 编码序列及其对CV基因表达的影响分析 人类。 (5) 对一组优先的基因工程小鼠进行分析 保守的非编码元件在 CV 基因表达中的作用。 (6) 为心血管研究人员建立教育计划 基因组数据库和工具的使用。

Disorders of the cardiovascular (CV) system are frequently due to temporal or quantitative changes in the expression of a large, but finite set of genes. Noncoding cis regulatory sequences play a central role in controlling gene expression and inter-species (i.e., human/mouse) genomic sequence comparisons serve as a rapid and accurate means for identifying such noncoding regulatory elements. The central goal of this PGA will be to use a comparative genomic approach first to identify, and them to determine the function of elements regulating the expression of genes affecting the CV system. The activities of this PGA are not centered on the discovery of new genes, but rather upon using comparative genomics to understand the role of cis regulating elements in the expression of genes already being studied by CV researchers. In this integrated program to "genomically" explore the regulation of CV genes, 200 human genomic intervals (=~200 BACs), each containing a CV gene(s), will be comparatively characterized. The components of this program will include: (1) The acquisition of orthologous human/mouse and other mammalian genomic sequence for a set of prioritized CV genes. Sequences will either be accessed from publicly funded databases or generated by the sequencing component of this PGA. (2) The creation of a cardiovascular comparative genomic database that will contain extensively annotated human and mouse sequences including the localization of conserved noncoding elements in proximity to well studied CV genes. (3) Genome-wide expression profiling to discover genes co-regulated with CV genes and identify shared noncoding regulatory elements, through intra-species analysis. (4) The identification of SNPs within conserved non- coding sequences, and analysis of their effect on CV gene expression in humans. (5) Analysis in genetically engineered mice of a prioritized set of the conserved noncoding elements for their role in CV gene expression. (6) The establishment of an educational program for cardiovascular researchers in the use of genomic databases and tools.