Genome-wide analysis of genetic variation expression

遗传变异表达的全基因组分析

• 批准号: 7117862
• 负责人: Richard S SPIELMAN
• 金额: $ 69.41万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-30 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7117862
• 关键词: clinical research; family genetics; gene expression; genetic mapping; genetic polymorphism; genetic regulatory element; genome; genomic imprinting; human genetic material tag; human population genetics; human tissue; microarray technology; molecular biology information system; open reading frames; polymerase chain reaction; single nucleotide polymorphism; telomere; transposon /insertion element

DESCRIPTION (provided by applicant): The objective of this study is the genetic analysis of gene expression as a phenotype in humans. The overall goals are to measure gene expression and characterize its variation in human cells, and to identify the genetic determinants of this variation. The specific aims for this renewal application are: 1) Determine the gene expression phenotypes of individuals in the CEPH families, 2) Map the determinants of variation in gene expression for several thousand genes, and 3) Identify and characterize the genetic determinants of variation in gene expression. In the last two years, we have identified a set of genes whose expression levels vary among unrelated individuals, and shown that there is a genetic component to this variation. In this renewal application, we will first complete the expression phenotyping of individuals in 59 families. Using the SNP genotypes for the same individuals, we will map the genetic determinants of the expression phenotypes by genome-wide linkage analysis and TDT methods (for fine mapping by linkage disequilibrium). Once we have identified candidate regions, we will identify the transcriptional regulators and functional variants in these regions using a combination of computational and molecular techniques. We expect to identify the gene and gene products involved in the complex network of transcriptional regulation, and to begin to describe the relationship between them. The approaches used in this project will allow us to understand better how transcription is regulated and to integrate genome variation at the level of RNA expression with that at the DNA sequence level. This work also has important implications for human disease, since some polymorphic variants that affect gene expression level are associated with disease susceptibility.

描述(申请人提供)：这项研究的目标是对基因表达作为人类表型的遗传分析。总体目标是测量基因在人类细胞中的表达并表征其变异，并确定这种变异的遗传决定因素。这一更新应用的具体目的是：1)确定CEPH家族中个体的基因表达表型，2)定位数千个基因的基因表达变异的决定因素，以及3)识别和表征基因表达变异的遗传决定因素。在过去的两年里，我们已经确定了一组基因，它们的表达水平在不同的无关个体之间存在差异，并表明这种差异存在遗传因素。在这次的续展申请中，我们将首先完成59个家庭的个体的表达表型。利用相同个体的SNP基因型，我们将通过全基因组连锁分析和TDT方法(通过连锁不平衡进行精细定位)来定位表达表型的遗传决定因素。一旦我们确定了候选区域，我们将使用计算和分子技术相结合的方法来确定这些区域中的转录调节因子和功能变体。我们期望确定参与转录调控的复杂网络中的基因和基因产物，并开始描述它们之间的关系。该项目中使用的方法将使我们能够更好地了解转录是如何调控的，并将基因组变异在RNA表达水平和DNA序列水平上整合起来。这项工作对人类疾病也有重要意义，因为一些影响基因表达水平的多态变异与疾病易感性有关。