P/HAD Genome Project (PHGP)

P/HAD 基因组计划 (PHGP)

• 批准号: 8777050
• 负责人: FENG C. ZHOU
• 金额: $ 19.73万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8777050
• 关键词: Accounting; Address; Alcohol consumption; Alcoholism; Alcohols; Alleles; Amino Acid Sequence; Breeding; Code; Cytosine; Epigenetic Process; Frequencies; Gene Expression; Generations; Genes; Genetic; Genetic Determinism; Genetic Polymorphism; Genetic Variation; Genome; Genomics; Goals; Heavy Drinking; Human; Indiana; Lead; Methylation; Modeling; Mutation; Nature; Pathogenesis; Pathway interactions; Peptide Sequence Determination; Rattus; Research; Resolution; Rewards; Technology; Thymine; Transcript; Uncertainty; Variant; alcohol response; alcohol seeking behavior; assault; base; differential expression; drinking behavior; endophenotype; epigenome; epigenomics; genetic variant; next generation sequencing; preference; sample fixation; success; trait; transcriptome sequencing

The high alcohol preference trait displayed by Indiana's selectively bred P and HAD1-2 rat lines models an important endophenotype of human alcoholism. Our long-term goal is to use these rat models to identify genomic signatures and illuminate CNS pathways that underile alcohol preference. By Integrating unbiased genomic analyses described here with traditional hypothesis-driven research done by others, we fully expect to open up exciting new windows on the pathogenesis of alcoholism. The central hypothesis is that both genomic and epigenomic mechanisms account for the variation in alcohol preference. Over the last 15 years, we have some success in locating a number of major QTLs and identifying several likely genes that contribute to alcohol preference using our rat models; however, there are uncertainties and many questions remain unanswered. We now want to exploit next generation sequencing (NGS) technologies to better understand the genomic signatures of selection and the interactions between genetic changes and environmental assaults that contribute to excessive alcohol consumption. By taking advantage of NGS studies, we can significantly increase the level of resolution and power of analysis to explain a greater portion of the genetic variation in alcohol preference in these rat models, to localize the genetic variations to genes and even down to SNPs, and to examine the potential importance of the epigenome on alcohol preference. The Specific Aims (SAs) are: SAI-To identify the genomic signatures of bi-directional selection (i.e. marks of selection) that explain the contrasting alcohol preference in the P/NP and HAD1-2/LAD1-2 rat lines. SA2-To delineate potentially causative variations in the selected regions identified in SA1 by searching for coding and regulatory differences associated with allele-specific expression (ASE). SA3-To examine the effects of parental alcohol use on Cytosine to Thymine transitions and their association with ASE. Through these studies, we expect to discover several hundred regions of selection that lead to functional consequences (altered gene expression and ASE) in the reward circuit, and ultimately uncover the coordinated genetic mechanisms that underlie the multifactorial nature of alcohol preference.

印第安纳州有选择性的繁殖P和1-2鼠线模型表现出的高酒精偏好特征 人类酒精中毒的重要内表型。我们的长期目标是使用这些老鼠模型来识别 基因组特征和阐明了不足的酒精偏爱的CNS途径。通过整合公正 此处描述的基因组分析是通过他人进行的传统假设驱动的研究，我们完全期望 为酒精中毒的发病机理打开令人兴奋的新窗口。中心假设是 基因组和表观基因组机制解释了酒精偏爱的变化。在过去的15年中， 我们在定位许多主要QTL方面取得了成功，并确定了几个可能的基因 使用我们的大鼠模型有助于酒精偏爱；但是，有不确定性和许多问题 保持没有答复。我们现在想利用下一代测序（NGS）技术来更好 了解选择的基因组特征以及遗传变化与 环境攻击导致过度饮酒。通过利用NGS 研究，我们可以显着提高分析和分析能力的水平，以解释更大的 在这些大鼠模型中，酒精偏好的遗传变异的一部分，将遗传变异定位到 基因，甚至是SNP，并检查表观基因组对酒精的潜在重要性 偏爱。具体目的（SAS）是：SAI识别双向选择的基因组特征 （即选择的标记）解释了P/NP中的对比鲜明的酒精偏好和HAD1-2/LAD1-2大鼠 线。 SA2到划定SA1中所选区域的潜在原因变化 寻找与等位基因特异性表达（ASE）相关的编码和调节差异。 sa3-to 检查父母饮酒对胞嘧啶对胸腺嘧啶转变的影响及其与它们的关联 ASE。通过这些研究，我们希望发现几百个导致的选择区域 奖励电路中的功能后果（基因表达和ASE），并最终发现 协调的遗传机制是酒精偏爱的多因素性质的基础。