Genome-wide analysis of genetic variation and expression.

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，并确定基因表达的遗传决定因素 变种。此续订申请的具体目标是：目标1.扩展材料和测试复制 在一个独立的家庭样本中存在联系/关联。目的2.开展家族性差异研究 等位基因表达。目的3.确定转录调控区域的特征。 在目前为期三年的拨款的头两年，我们已经确定了基因的表达 对大约40个大家庭的成员的表型进行了连锁分析，以确定 染色体定位与每种表型相关联。这些发现得到了全基因组关联的跟进。 用SNP基因型别分析国际HapMap样本中的基因表达表型 项目。在这次续签申请中，我们将把我们的基因研究扩展到另外45个家庭。新的 表型数据以及相同个体的SNP基因类型将用于评估复制 来自最初的全基因组连接和关联分析的发现，并加强证据 结果是积极的。为了补充我们从连锁和关联中发现的差异等位基因表达， 我们将对同卵双胞胎及其家庭成员进行等位基因不平衡分析。通过测量 从一个基因的两个等位基因的转录本表达，我们可以直接评估顺式作用的调控 对基因表达的影响。这些分析的结果揭示了自然界中广泛的变异性 以及等位基因失衡的程度。我们以家庭为基础的方法将使我们能够评估相对贡献 遗传的顺式和反式调节子，以及印记，这种可变性。一旦我们确定了候选人 包含顺式和/或反式转录调控因子的区域，我们将执行分子 这些区域的特征，以确定导致观察到的 基因表达的变异，并确定其调控机制。 基因表达是DNA序列与包括疾病在内的表型变异之间的纽带。我们的 这种方法将使我们能够表征人类的基因表达变异，并理解转录 通过识别转录调控因子进行控制。基因表达水平也是其他 数量性状。因此，这里发展的分子和分析方法可以推广。 并应用于人类其他数量性状的研究，包括复杂的遗传病。

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.