Genome-wide analysis of genetic variation and expression.

遗传变异和表达的全基因组分析。

• 批准号: 7683920
• 负责人: Vivian G Cheung
• 金额: $ 74.32万
• 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 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7683920
• 关键词: Alleles; Allelic Imbalance; Biological; Complement; Complex; DNA Sequence; Data; Disease; Family; Family Study; Family member; Funding; Gene Expression; Genes; Genetic; Genetic Determinism; Genetic Variation; Goals; Grant; Hereditary Disease; Human; Individual; Inherited; International; Link; Location; Maps; Materials Testing; Measures; Molecular; Monozygotic Twinning; Monozygotic twins; Nature; Nucleic Acid Regulatory Sequences; Phenotype; Regulatory Element; Relative (related person); SNP genotyping; Sample Size; Sampling; Transcript; Transcriptional Regulation; Variant; base; follow-up; genetic analysis; genetic linkage analysis; genome wide association study; genome-wide analysis; genome-wide linkage; imprint; member; trait

The focus of this study is the genetics of variation in human gene expression. Our overall goals are to characterize the extent of variation in gene expression and to identify the genetic determinants of this variation. The specific aims for this renewal application are: Aim 1. Expand materials and test for replication of linkage/association in an independent sample of families. Aim 2. Carry out family studies of differential allelic expression. Aim 3. Characterize the transcriptional regulatory regions. In the first two years of the current three-year grant, we have determined the gene expression phenotypes of members of approximately40 large families and carried out linkage analysis to determine the chromosomal location linked to each phenotype. The findings were followed up by genome-wide association analysis of the expression phenotypes, using SNP genotypes in samples from the International HapMap Project. In this renewal application, we will extend our genetic study to 45 additional families. The new phenotype data, along with SNP genotypes of the same individuals, will be used to evaluate replication of findings from the original genome-wide linkage and association analyses, and to strengthen the evidence for positive results. To complement our findings of differential allelic expression from linkage and association, we will carry out analysis of "allelic imbalance" in monozygotic twins and family members. By measuring the expression of transcripts from the two alleles of a gene, we get a direct assessment of cis-acting regulatory effects on gene expression. Results from such analyses have revealed extensive variability in the nature and extent of allelic imbalance. Our family-based approach will allow us to assess the relative contributions of inherited cis and trans regulators, and of imprinting, to this variability. Once we have identified candidate regions that contain cis- and/ or trans-acting transcriptional regulators, we will perform molecular characterization of those regions in order to identify the sequence variants responsible for the observed variation in gene expression, and determine the regulatory mechanisms. Gene expression is the link between DNA sequence and phenotype variation, including disease. Our approach will allow us to characterize gene expression variation in humans and to understand transcriptional control by identifying transcriptional regulators. The level of gene expression is also a paradigm for other quantitative traits. Therefore, the molecular and analytical approaches developed here can be generalized and applied to the study of other quantitative traits in humans, including complex genetic diseases.

这项研究的重点是人类基因表达变异的遗传学。我们的总体目标是 表征基因表达的变异程度并确定其遗传决定因素 变化。此续签应用的具体目的是：AIM 1。扩展材料并进行复制测试 独立家庭样本中的连锁/关联。目标2。进行差异的家庭研究 等位基因表达。目标3。特征转录调节区域。 在当前三年赠款的头两年中，我们确定了基因表达 大约40个大家庭的成员的表型并进行了连锁分析以确定 染色体位置与每个表型相关。调查结果是全基因组关联的随后 使用国际HAPMAP样品中的SNP基因型对表达表型的分析 项目。在此续签应用中，我们将把我们的遗传研究扩展到其他45个家庭。新的 表型数据以及同一个体的SNP基因型将用于评估复制 来自原始基因组联系和关联分析的发现，并加强证据 积极的结果。为了补充我们从链接和关联中差异等位基因表达的发现， 我们将对单卵双胞胎和家庭成员中的“等位基因失衡”进行分析。通过测量 来自基因两个等位基因的转录本的表达，我们可以直接评估顺式作用调节 对基因表达的影响。这种分析的结果揭示了性质的广泛差异 和等位基因失衡的程度。我们基于家庭的方法将使我们能够评估相对的贡献 遗传的顺式和跨性别调节剂以及印迹的变异性。一旦我们确定了候选人 包含顺式和/或反式转录调节器的区域，我们将执行分子 这些区域的表征是为了识别负责观察到的序列变体 基因表达的变化，并确定调节机制。 基因表达是DNA序列与表型变异之间的联系，包括疾病。我们的 方法将使我们能够表征人类的基因表达变异并理解转录 通过识别转录调节器来控制。基因表达水平也是其他的范式 定量特征。因此，这里开发的分子和分析方法可以推广 并应用于人类中其他定量性状的研究，包括复杂的遗传疾病。