Integrated GWAS of complex behavioral and gene expression traits in outbred rats

远交大鼠复杂行为和基因表达特征的综合 GWAS

• 批准号: 9053471
• 负责人: ABRAHAM A PALMER
• 金额: $ 263.22万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-15 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9053471
• 关键词: Address; Alleles; Animal Experimental Psychology; Behavior; Behavioral; Behavioral Paradigm; Brain region; Breeding; Buffaloes; Candidate Disease Gene; Chicago; Cocaine; Communities; Complex; Cues; DNA; DNA Sequencing Facility; Data; Development Plans; Drug abuse; Education; Education and Outreach; Faculty; Female; Fostering; Funding; Gene Expression; Gene Mutation; Generations; Genes; Genetic; Genetic Predisposition to Disease; Genetic Recombination; Genetic Techniques; Genetic study; Genotype; Goals; Haplotypes; Health Sciences; Heritability; Human; Human Genome; Impulsivity; Inbred Strains Rats; Inbreeding; Individual; Intake; Maps; Measures; Mental disorders; Methods; Michigan; Mission; Modeling; Molecular; Mus; National Institute of Drug Abuse; Neurosciences; Nicotine; Performance; Pharmaceutical Preparations; Phenotype; Pilot Projects; Population; Postdoctoral Fellow; Process; Progress Reports; Quantitative Genetics; Quantitative Trait Loci; RNA; Rattus; Regulation; Research; Research Design; Research Institute; Research Personnel; Research Project Grants; Resources; Rewards; Risk; Sampling; Self Administration; Sex Characteristics; Single Nucleotide Polymorphism; Social Environment; Statistical Methods; Techniques; Tennessee; Training; United States National Institutes of Health; Universities; Variant; Wisconsin; Wood material; addiction; base; behavior influence; behavior measurement; behavioral study; career development; classical conditioning; cost; drug seeking behavior; follow-up; genome wide association study; genome-wide; graduate student; high school; improved; incentive salience; innovation; insight; male; medical schools; member; next generation; next generation sequencing; outreach; outreach program; pleiotropism; preference; programs; psychologic; public health relevance; research and development; reverse genetics; sex; tool; trait; transcriptome sequencing; undergraduate student

DESCRIPTION (provided by applicant): We will use quantitative genetic techniques to identify genes and alleles that influence a constellation of psychologically complex behavioral phenotypes that are associated with drug abuse. Our center capitalizes on a number of recent advances in study design, next-generation sequencing and statistical methods that together create an exceptional opportunity. Whereas the past two decades have seen enormous advances in both forward (phenotype to genotype) and reverse (genotype to phenotype) genetic studies in mice, there has been much less progress developing and applying the same techniques in rats. Although both forward and reverse genetic studies in mice have been extremely fruitful, many important but complex psychological processes are difficult or impossible to study in mice. For this reason we are proposing to adapt a variety of genetic techniques that we have already used successfully in mice, for behavioral studies in rats. In the current application, we propose to employ state-of-the-art tools to elucidate the genetic basis of a variety of behaviors that are relevant to drug abuse in 4,800 rats. A key strength of our center is that we utilize a unique rat heterogeneous stock (HS). These rats, sometimes referred to as N/NIH, are an HS that was created in 1984 by intercrossing 8 inbred rat strains and have been maintained as an outbred population for 65 generations. This has given rise to numerous accumulated recombinations that make them an ideal resource for performing studies that are analogous to human genome wide association studies (GWAS). Significantly, all 8 inbred founder strains have recently been re-sequenced, identifying 7.2 million SNPs. We will genotype these rats using an innovative next-generation sequencing-based method that provides ~100K SNPs at an extremely low cost. We will use these data to infer haplotypes, which will allow us to impute all 7.2 million SNPs in each rat. In addition to identifying associations between these SNPs and the behavioral traits, we will also examine gene expression in 72 behaviorally naive rats focusing on 4 key brain regions. We will use these data to identify expression quantitative trait loci (eQTLs). We will then integrate all of these data to identify specific genes that influece behavior. Many of the behavioral domains being studied are known to be sexually dimorphic; our study will use both male and female rats, which will allow us to identify sex differences and sex by genotype interactions. We will also identify co-heritability among these traits, as well as pleiotropic effects of individual loci on multiple putatively related behavioral domains. Finally, the proposed center includes numerous educational, career development and public outreach activities. We will implement a program to train high school and undergraduate students. In addition, technicians, graduate students, postdocs and junior faculty will receive career development advice in the form of individual development plans and research performance progress reports. Finally, we will engage in public outreach programs that will draw on diverse communities in Chicago, Buffalo and Memphis.

描述（由申请人提供）：我们将使用定量遗传技术来识别影响与药物滥用相关的一系列心理复杂行为表型的基因和等位基因。我们的中心利用了研究设计、下一代测序和统计方法方面的许多最新进展，共同创造了一个特殊的机会。尽管过去二十年在小鼠的正向（表型到基因型）和反向（基因型到表型）遗传研究方面取得了巨大进展，但在大鼠中开发和应用相同技术的进展却要少得多。尽管小鼠的正向和反向遗传学研究都非常富有成果，但许多重要但复杂的心理过程很难或不可能在小鼠身上进行研究。出于这个原因，我们建议采用我们已经在小鼠身上成功使用的各种遗传技术来进行大鼠的行为研究。在当前的应用中，我们建议采用最先进的工具来阐明 4,800 只老鼠与药物滥用相关的各种行为的遗传基础。我们中心的一个关键优势是我们利用独特的大鼠异种库存 (HS)。这些大鼠有时称为 N/NIH，是 1984 年通过 8 个近交系大鼠杂交产生的 HS，并作为远交群体维持了 65 代。这导致了大量累积的重组，使它们成为进行类似于人类基因组广泛关联研究（GWAS）的研究的理想资源。值得注意的是，所有 8 个近交创始人品系最近均已重新测序，鉴定出 720 万个 SNP。我们将使用创新的下一代基于测序的方法对这些大鼠进行基因分型，该方法以极低的成本提供约 100K SNP。我们将使用这些数据来推断单倍型，这将使​​我们能够估算每只大鼠的所有 720 万个 SNP。除了确定这些 SNP 与行为特征之间的关联外，我们还将检查 72 只行为幼稚大鼠的基因表达，重点关注 4 个关键大脑区域。我们将使用这些数据来识别表达数量性状基因座 (eQTL)。然后我们将整合所有这些数据来识别影响行为的特定基因。众所周知，正在研究的许多行为领域都具有性别二态性。我们的研究将使用雄性和雌性大鼠，这将使我们能够通过基因型相互作用来识别性别差异和性别。我们还将确定这些性状之间的共同遗传性，以及单个基因座对多个假定相关的行为领域的多效性影响。 最后， 拟议的中心包括许多教育、职业发展和公共外展活动。我们将实施高中生和本科生培养计划。此外，技术人员、研究生、博士后和初级教师将以个人发展计划和研究绩效进度报告的形式获得职业发展建议。最后，我们将参与公共外展计划，吸引芝加哥、布法罗和孟菲斯的不同社区。