Characterizing the developing human brain transcriptome at single-base resolution

以单碱基分辨率表征发育中的人脑转录组

• 批准号: 9264591
• 负责人: Andrew Ellis Jaffe
• 金额: $ 27.39万
• 依托单位: LIEBER INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9264591
• 关键词: Age; Aging; Alzheimer' s Disease; Autopsy; Big Data; Brain; Brain Diseases; Brain region; Cell Line; Clinical; Code; Computer software; Conserved Sequence; DNA Methylation; Data; Data Analyses; Data Set; Databases; Dependence; Development; Developmental Process; Dissection; Epigenetic Process; First Pregnancy Trimester; Gene Expression; Genes; Genetic Risk; Genetic Transcription; Genome; Genomic Segment; Genomics; Genotype; Goals; Human; Institutes; Life; Longevity; Major Depressive Disorder; Measurement; Medical Genetics; Mental disorders; Methods; Microarray Analysis; Mus; Parkinson Disease; Pattern; Pilot Projects; Play; Process; RNA; RNA analysis; Regulation; Research Personnel; Resolution; Resources; Risk; Role; Sampling; Schizophrenia; Scientist; Signal Transduction; Specificity; Technology; Testing; Transcript; Validation; aged; analytical tool; base; brain tissue; clinical risk; clinically relevant; clinically significant; design; differential expression; experimental study; fetal; frontal lobe; genome wide association study; genome-wide; genomic tools; improved; insight; interest; novel; public health relevance; risk variant; secondary analysis; tool; trait; transcriptome; transcriptome sequencing

 DESCRIPTION (provided by applicant): Human post-mortem brain tissue provides a valuable resource for identifying expression-based determinants of development and subsequent dysregulation in brain disorders (Kleinman 2011). RNA sequencing (RNA-seq) generates potentially unbiased characterization of the transcriptome, and has now been performed on over 1,000 non-psychiatric human brain samples across the lifespan within our lab (LIBD) and via the BrainSpan project (www.brainspan.org). We propose to combine and re-process these data together to make them more comparable, starting from raw sequencing reads. Our goal is further interrogate the clinical relevance of developmentally dynamic regions of gene expression across brain development. Our preliminary RNAseq data demonstrates extensive developmental regulation of previously unannotated intra- and inter-genic sequence conserved across multiple brain regions in both humans and mice. Base-level analysis of these combined RNA-seq data can greatly improve existing gene annotation databases like Ensembl and UCSC, which currently lack many fetal brain-specific transcripts that we have identified and characterized in our samples. We will perform base-level resolution analyses on both the entire dataset, from first trimester of fetal life through the aged (>85 years), and then secondary analyses exploring differential expression across different brain regions, to identify dynamic expressed sequence. Identified differentially expressed regions (DERs) will be interrogated for clinical significance through enrichment analysis with regard to predefined clinical gene sets, for examples significant loci from genome-wide association studies (GWAS) for brain disorders like schizophrenia, and also by directly associating genetic risk with expression levels within identified DERs. We will further provide the genomic tools to allow researchers with interests in other genes and loci to design their own validation experiments in cell lines and/or primary brain tissue for these clinically relevant loci. A more comprehensive characterization of the human brain transcriptome, leveraging "big data" across two complementary datasets, will be valuable for scientists studying a wide range of developmental processes and brain disorders.

 描述（应用程序提供）：人类后验尸脑组织为识别基于表达的发育确定和随后的脑部疾病失调的确定提供了宝贵的资源（Kleinman 2011）。 RNA测序（RNA-SEQ）产生了转录组的潜在无偏表征，现在已经对我们实验室（LIBD）的整个生命周期和Brainspan Project（www.brainspan.org）进行了1,000多个非精神病患者脑样本。我们建议将这些数据合并并重新处理这些数据，以使它们更具可比性，从原始测序读取开始。我们的目标是进一步询问整个大脑发育中基因表达发展动态区域的临床相关性。我们的初步RNASEQ数据表明，在人类和小鼠的多个大脑区域中保守的先前未经宣传的内部和基因间序列的广泛发育调节。对这些组合的RNA-seq数据的基础级分析可以大大改善现有的基因注释数据库，例如Ensembl和UCSC，这些数据库目前缺乏我们在样本中鉴定和表征的许多胎儿脑特异性转录本。我们将对整个数据集进行基础分辨率分析，从胎儿生命的头三个月到老化（> 85年），然后二级分析探索不同大脑区域的差异表达，以识别动态表达的序列。确定的不同表达区域（DER）将通过关于预定义的临床基因集的富集分析来审问有关临床意义的临床意义。 示例来自基因组关联研究（GWAS）的重要地方，例如精神分裂症等脑部疾病，以及将遗传风险与已识别的DER中的表达水平直接关联。我们将进一步提供基因组工具，以允许对其他基因和Locali感兴趣的研究人员在细胞系和/或原发性脑组织中为这些临床相关的局部设计自己的验证实验。人脑转录组的更全面的表征，利用两个完整数据集的“大数据”，对于研究广泛的发育过程和脑部疾病的科学家来说是有价值的。

项目成果

regionReport: Interactive reports for region-level and feature-level genomic analyses.

RegionReport：用于区域级和特征级基因组分析的交互式报告。

• DOI: 10.12688/f1000research.6379.2
• 发表时间: 2015
• 期刊: F1000Research
• 作者: Collado-Torres,Leonardo;Jaffe,AndrewE;Leek,JeffreyT
• 通讯作者: Leek,JeffreyT

Flexible expressed region analysis for RNA-seq with derfinder.

• DOI: 10.1093/nar/gkw852
• 发表时间: 2017-01-25
• 期刊: Nucleic acids research
• 影响因子: 14.9
• 作者: Collado-Torres L;Nellore A;Frazee AC;Wilks C;Love MI;Langmead B;Irizarry RA;Leek JT;Jaffe AE
• 通讯作者: Jaffe AE

recount workflow: Accessing over 70,000 human RNA-seq samples with Bioconductor.

• DOI: 10.12688/f1000research.12223.1
• 发表时间: 2017-01-01
• 期刊: F1000Research
• 作者: Collado-Torres, Leonardo;Nellore, Abhinav;Jaffe, Andrew E
• 通讯作者: Jaffe, Andrew E