Genome-wide analysis of genetic variation and expression.

描述(申请人提供)：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，并确定这种变异的遗传决定因素。这一续展申请的具体目的是：目的1.扩大材料，并在一个独立的家族样本中测试连锁/关联的重复性。目的2.开展等位基因差异表达的家系研究。目的3.确定转录调控区域的特征。 在本次为期三年的资助的头两年，我们已经确定了大约40个大家庭成员的基因表达表型，并进行了连锁分析，以确定与每个表型连锁的染色体位置。随后，利用国际HapMap项目样本中的SNP基因型，对表达表型进行了全基因组关联分析。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，将被用来评估最初全基因组链接和关联分析结果的重复性，并加强阳性结果的证据。为了补充我们从连锁和关联方面的差异等位基因表达的发现，我们将对同卵双胞胎和家庭成员进行等位基因不平衡分析。通过测量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对基因表达的调控作用。这些分析的结果显示，等位基因不平衡的性质和程度存在广泛的变异性。我们基于家庭的方法将使我们能够评估遗传顺式和反式调节因子以及印记对这种变异性的相对贡献。一旦我们确定了包含顺式和/或反式转录调控因子的候选区域，我们将对这些区域进行分子表征，以确定导致所观察到的基因表达变化的序列变体，并确定调控机制。 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。我们的方法将使我们能够表征人类的基因表达变异，并通过识别转录调控因子来了解转录调控。基因表达水平也是其他数量性状的范例。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。

DESCRIPTION (provided by applicant): 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 approximately 40 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.