The Heritable Transcriptome and Alcoholism

可遗传转录组和酗酒

• 批准号: 9339832
• 负责人: Paula Hoffman
• 金额: $ 58.31万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-05 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9339832
• 关键词: 3' Untranslated Regions; Acetates; Alcohol consumption; Alcoholism; Alcohols; Animal Genetics; Animal Model; Animals; Behavior; Behavioral; Binding; Binding Sites; Biochemistry; Biological Models; Brain; Brown Fat; Candidate Disease Gene; Cells; Chromosome Mapping; Clinical; Code; Communities; Complex; DNA Sequence; Data; Data Analyses; Data Set; Databases; Development; Disease; Elements; Embryo; Environment; Environmental Exposure; Epidemiology; Estrus; Ethanol Metabolism; Exons; Factor Analysis; Female; Gene Cluster; Gene Expression; Generations; Genes; Genetic; Genetic Heterogeneity; Genetic Predisposition to Disease; Genetic Transcription; Genetic Variation; Genetic study; Genome; Genomics; Goals; Grant; Heart; Heritability; Human; Human Genome; Hybrids; Inbred Strain; Inbred Strains Rats; Inbreeding; Individual; Informatics; Laboratories; Light; Link; Liver; Maps; Measures; Mental Depression; Methods; MicroRNAs; Molecular; Mus; Organ; Organism; Other Genetics; Phenotype; Physiological; Play; Polyadenylation; Polygenic Traits; Population; Predisposing Factor; Predisposition; Process; Protein Isoforms; Publishing; Quantitative Trait Loci; RNA; RNA Sequences; Rat Strains; Rattus; Recombinant Inbred Strain; Recombinants; Regulator Genes; Research; Resources; Resuscitation; Rodent; Role; Scientist; Site; Stable Populations; Swimming; System; Systems Analysis; Techniques; Testing; Tissues; Training; Transcript; Untranslated RNA; Visualization software; Wisconsin; Work; addiction; alcohol use disorder; animal data; base; cognitive ability; data acquisition; depression model; deprivation; design; endophenotype; gene environment interaction; gene product; genetic analysis; genetic approach; genetic association; genetic variant; genome database; genome wide association study; genomic data; human disease; insight; interest; male; medical schools; novel; protein metabolite; rat genome; sex; trait; transcriptome; web portal; web site; whole genome

The goal of this application is to establish an animal model and accompanying database suitable for a systems genetic analysis of complex traits, specifically traits that represent genetic predisposing factors for alcohol use disorder (AUD). Systems genetic approaches require a global analysis of factors such as gene expression, protein and metabolite levels in multiple tissues of an organism, as well as an understanding of gene-gene and gene-environment interactions, and the interdependency of these factors in contributing to complex traits/disorders. As a result, a key requirement for an animal model is a genetically stable population that can be studied repeatedly, over many generations, to provide cumulative data that can eventually allow for a complete systems genetic analysis. During the past grant periods, we have progressed well with the development of a Hybrid Rat Diversity Panel (HRDP) that meets these criteria. We have chosen to focus on the rat, rather than the mouse, for studies of complex traits related to AUD, because of the greater size of the rat brain, the ease of training in operant tasks, and the rat’s higher cognitive ability. We have generated DNA sequence data, RNA sequence data and whole genome exon array data on four tissues (brain, liver [whole organ and cell-specific data], heart and brown adipose tissue) from rat strains of the HXB/BXH recombinant inbred (RI) panel and from classic inbred rat strains. We have mapped QTLs for behavioral/physiological traits (alcohol consumption, alcohol deprivation effect, alcohol metabolism including acetate levels after alcohol administration), as well as used transcriptome data to map expression QTLs, to generate transcript coexpression modules and map module eigengene (first principal component) QTLs. These data have been used to identify candidate genes and transcriptional networks that contribute to the measured biochemistry and behaviors. All of our raw, processed and analyzed data have been made available to the research community on our PhenoGen website (http://phenogen.ucdenver.edu). This website, that we developed, also includes several visualization tools to explore these data in a systems genetics framework and allows the user to observe genetic relationships between a complex phenotype of interest and networks of gene products that influence the phenotype. We are now proposing to complete the main core of transcriptional data for the 96- strain HRDP, adding data from another rat RI panel (FXLE/LEXF) and more inbred rat strains. We will obtain full transcriptome information of brain and liver of male and female rats from all strains, quantify the expression of transcript isoforms, including 3’UTR isoforms, and analyze the 3’UTR regions for alternative use of polyadenylation sites and miRNA binding sites. We will use our established and newly developed pipelines to disseminate integrated, systems level data (PhenoGen and Rat Genome Database). We will also expand our demonstration for applying the gathered information to the identification of genetic factors that are linked to the development of AUD by obtaining information on predisposition to “depression” in the HXB/BXH RI panel, and we will continue to integrate the animal data with human GWAS data.

本申请的目的是建立一个适合于系统的动物模型和相应的数据库 复杂性状的遗传分析，特别是代表酒精使用遗传易感因素的性状 疾病（AUD）。系统遗传学方法需要对基因表达， 蛋白质和代谢物水平在生物体的多个组织，以及基因的理解， 基因与环境的相互作用，以及这些因素的相互依赖性， 性状/障碍。因此，动物模型的关键要求是遗传稳定的种群， 反复研究，经过许多代，以提供累积的数据，最终可以允许一个 完整的系统遗传分析。在过去的资助期内，我们在 开发符合这些标准的杂交大鼠多样性小组（HRDP）。我们选择专注于 大鼠，而不是小鼠，用于研究与AUD相关的复杂性状，因为大鼠的体积更大， 老鼠的大脑，易于训练的操作任务，和老鼠的更高的认知能力。我们已经生成了DNA 四种组织（脑、肝[全]）的序列数据、RNA序列数据和全基因组外显子阵列数据 器官和细胞特异性数据]、心脏和棕色脂肪组织） 近交系（RI）组和来自经典近交系大鼠品系。我们已经定位了行为/生理性状的QTL （酒精消耗，酒精剥夺效应，酒精代谢，包括酒精后的乙酸水平） 施用），以及使用转录组数据来定位表达QTL，以产生转录本。 共表达模块和图谱模块特征基因（第一主成分）QTL。这些数据已 用于识别有助于测量的生物化学的候选基因和转录网络， 行为。我们所有的原始，处理和分析数据都已提供给研究界 在我们的PhenoGen网站（http：//www.example.com）上。phenogen.ucdenver.edu我们开发的这个网站还包括 几个可视化工具，在系统遗传学框架中探索这些数据，并允许用户 观察感兴趣的复杂表型和基因产物网络之间的遗传关系， 影响表型。我们现在建议完成96- 99年的主要核心转录数据， HRDP品系，添加来自另一大鼠RI组（FXLE/LEXF）和更多近交系大鼠品系的数据。我们将获得 所有品系雄性和雌性大鼠脑和肝脏的全转录组信息，定量表达 转录物同种型，包括3 'UTR同种型，并分析3' UTR区域的替代用途， 多聚腺苷酸化位点和miRNA结合位点。我们将利用现有和新开发的管道， 传播综合的系统级数据（PhenoGen和大鼠基因组数据库）。我们还将扩大我们的 示范应用所收集的信息，以确定遗传因素，是链接到 通过在HXB/BXH RI面板中获得关于“抑郁症”易感性的信息来发展AUD，以及 我们将继续整合动物数据和人类GWAS数据。