Genomic regulatory sequence analysis for alcohol-related phenotypes

描述(申请人提供)：酒精中毒相关特征的发展被认为是由遗传和环境因素以及它们之间的相互作用引起的。与酒精中毒相关的特征相关的遗传变异可以影响几种不同的机制，包括基因表达调控。这项工作的目标是研究哺乳动物模型系统，以确定有助于酒精相关行为转录变化的基因组调控序列。在哺乳动物中，由于这些元件的小和退化的性质以及哺乳动物基因组的复杂性和大小，在全基因组范围内探索调控序列是困难的。因此，这项拟议的研究将依靠来自多个不同数据来源的证据来帮助缩小对调控序列的搜索范围。首先，除了重组近交系的基因数据外，还将分析高通量的基因表达数据，以确定显示共同调控模式并与酒精相关表型相关的基因。然后，这些基因上游和下游共有的共同序列将被确定为潜在的调控元件。其次，将在选定的大鼠品系上进行基因表达实验，以便将它们与现有的小鼠酒精偏好研究进行比较。为了改进对潜在调控元件的搜索，将只考虑两个啮齿动物研究中的同源基因之间共享的共同表达模式和序列。这个项目被设计为一个有指导的研究机会，让候选人将她以前的经验和在研究转录调控的计算方法方面的培训应用到酒精研究中。候选人将利用获奖期发展这一努力所需的药理学、哺乳动物系统和基因组学方面的背景和技能。该项目的成果是开发大规模生物信息学方法，用于分析酒精相关性状模型系统中的基因表达研究、遗传数据和基因组序列。由此产生的方法和数据将向整个酒精研究社区提供。

DESCRIPTION (provided by applicant): The development of alcoholism related traits is believed to be caused by both genetic and environmental factors, in addition to their interactions. Genetic variations associated with alcoholism related traits can affect several different mechanisms, including gene expression regulation. The goal of this work is to study mammalian model systems to identify genomic regulatory sequences that contribute to transcriptional changes in alcohol-related behaviors. Genome-wide exploration of regulatory sequences is difficult in mammals because of the small and degenerate nature of these elements and because of the complexity and size of mammalian genomes. Therefore, the proposed study will rely on evidence from multiple different data sources to help narrow the search for regulatory sequences. First, high-throughput gene expression data in addition to genotypic data on recombinant inbred strains will be analyzed to identify genes that show common regulatory patterns and are correlated with alcohol related phenotypes. Then, common sequences shared in the upstream and downstream regions of these genes will be identified as potential regulatory elements. Second, gene expression experiments on rat selected lines will be performed so that they can be compared with existing mouse studies on alcohol preference. To improve the search for potential regulatory elements, only common expression patterns and sequences shared between orthologous genes in the two rodent studies will be considered. This project is designed as a mentored research opportunity for the candidate to apply her prior experience and training in computational approaches for studying transcription regulation to alcohol research. The candidate will use the award period to develop the background and skills in pharmacology, mammalian systems and genomics necessary for this endeavor. The outcome of this project is to develop large scale bioinformatics methods for analyzing gene expression studies, genetic data and genomic sequences in model systems of alcohol related traits. The resulting methods and data will be made available to the alcohol research community at large.