Genomic regulatory sequence analysis for alcohol-related phenotypes

描述（由申请人提供）：酒精中毒相关性状的发展被认为是由遗传和环境因素以及它们的相互作用引起的。与酒精中毒相关性状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，以确定基因组调控序列，有助于酒精相关行为的转录变化。在哺乳动物中对调控序列进行全基因组探索是困难的，因为这些元件的小和简并性质以及哺乳动物基因组的复杂性和大小。因此，拟议的研究将依赖于来自多个不同数据源的证据，以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型数据的高通量基因表达数据将进行分析，以确定基因，显示共同的监管模式，并与酒精相关的表型。然后，在这些基因的上游和下游区域共享的共同序列将被鉴定为潜在的调控元件。第二，将对大鼠选定的品系进行基因表达实验，以便将其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，将仅考虑两项啮齿动物研究中直向同源基因之间共有的共同表达模式和序列。该项目旨在为候选人提供一个指导性的研究机会，将她以前的经验和计算方法的培训应用于酒精研究的转录调控研究。候选人将利用奖励期间发展药理学，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的生物信息学方法，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提供给整个酒精研究界。

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.