Decoding the regulatory architecture of the human genome across cell types, individuals and disease

解码人类基因组跨细胞类型、个体和疾病的调控结构

• 批准号: 10241018
• 负责人: JONATHAN K PRITCHARD
• 金额: $ 61.95万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-01 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10241018
• 关键词: Architecture; Area; Cell model; Clustered Regularly Interspaced Short Palindromic Repeats; Code; Complex; Computer software; Computing Methodologies; Data; Disease; Funding; Gene Expression Regulation; Genetic Transcription; Genetic Variation; Genome; Genome Mappings; Human Genome; Individual; Link; Maps; Methods; Nucleic Acid Regulatory Sequences; Open Reading Frames; Output; Proteins; Regulator Genes; Resolution; Site; Validation; Variant; Work; Zinc Fingers; base; cell type; computerized tools; experimental study; gene function; genome wide association study

PROJECT DESCRIPTION While accurate annotations of protein-coding regions in the human genome have been available for many years, annotation and interpretation of regulatory sequences has lagged far behind. This is because—in contrast to protein-coding sequences—the “rules” that govern links from genome sequence to regulatory function are fuzzy, complex, and highly context-specific. Our limited understanding of regulatory regions presents a fundamental challenge for the identification and interpretation of disease variation, especially in the context of personal genome interpretation. Work from ENCODE and other groups has started to close this gap through experimental work, including high-resolution maps of regulatory sites in a variety of cell types, and modeling of the cell-type specific mappings from genome sequence to regulatory function. In our funded project so far we have developed new computational tools to understand gene regulation, and how this may be impacted by genetic variation; as well as new methods for high throughput validation. In the Supplement year, we propose to extend this work with additional projects focusing in this area, including work on zinc finger proteins; connections between genetic variation, RNA expression, and GWAS; and, finally, high throughput CRISPR-based validation experiments.

项目描述 虽然人类基因组中蛋白质编码区的准确注释已可用于 多年来，调控序列的注释和解释已经远远落后。 因为与蛋白质编码序列相比，控制基因组链接的“规则” 监管功能的顺序是模糊的、复杂的并且高度特定于环境。 对监管区域的理解对识别和监管区域提出了根本性的挑战。 疾病变异的解释，特别是在个人基因组解释工作的背景下。 ENCODE 和其他小组已经开始通过实验工作来缩小这一差距，包括 各种细胞类型中调控位点的高分辨率图谱以及细胞类型的建模 到目前为止，在我们资助的项目中，我们已经有了从基因组序列到调节功能的具体映射。 开发了新的计算工具来了解基因调控，以及基因调控如何受到影响 遗传变异；以及高通量验证的新方法。 建议通过专注于该领域的其他项目来扩展这项工作，包括锌指工作 蛋白质；遗传变异、RNA 表达和 GWAS 之间的联系； 基于 CRISPR 的验证实验的吞吐量。

项目成果

Properties of structural variants and short tandem repeats associated with gene expression and complex traits

• DOI: 10.1038/s41467-020-16482-4
• 发表时间: 2020-06-10
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Jakubosky, David;D'Antonio, Matteo;Frazer, Kelly A.
• 通讯作者: Frazer, Kelly A.

The Kipoi repository accelerates community exchange and reuse of predictive models for genomics

• DOI: 10.1038/s41587-019-0140-0
• 发表时间: 2019-06-01
• 期刊: NATURE BIOTECHNOLOGY
• 影响因子: 46.9
• 作者: Avsec, Ziga;Kreuzhuber, Roman;Gagneur, Julien
• 通讯作者: Gagneur, Julien

Discovering epistatic feature interactions from neural network models of regulatory DNA sequences.

• DOI: 10.1093/bioinformatics/bty575
• 发表时间: 2018-09-01
• 期刊: Bioinformatics (Oxford, England)
• 作者: Greenside P;Shimko T;Fordyce P;Kundaje A
• 通讯作者: Kundaje A

Discovery and quality analysis of a comprehensive set of structural variants and short tandem repeats

• DOI: 10.1038/s41467-020-16481-5
• 发表时间: 2020-06-10
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Jakubosky, David;Smith, Erin N.;Frazer, Kelly A.
• 通讯作者: Frazer, Kelly A.

fastISM: performant in silico saturation mutagenesis for convolutional neural networks.

fastISM：卷积神经网络的计算机模拟饱和诱变。

• DOI: 10.1093/bioinformatics/btac135
• 发表时间: 2022
• 期刊: Bioinformatics (Oxford, England)
• 作者: Nair,Surag;Shrikumar,Avanti;Schreiber,Jacob;Kundaje,Anshul
• 通讯作者: Kundaje,Anshul