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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

基本信息

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
项目类别：
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

项目摘要

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.

项目说明虽然人类基因组中蛋白质编码区的准确注释已经可以用于多年来，对调控序列的注释和解释一直远远落后。这是因为--与蛋白质编码序列不同--管理来自基因组的连接的“规则” 序列到调节功能是模糊的、复杂的，并且高度特定于上下文。我们的有限公司对监管区域的了解是确定和对疾病变异的解释，特别是在个人基因组解释的背景下。工作 Encode和其他组织已经开始通过实验工作缩小这一差距，包括各种细胞类型中调控位点的高分辨率地图，以及细胞类型的建模从基因组序列到调控功能的特定映射。到目前为止，在我们资助的项目中，开发了新的计算工具来理解基因调控，以及这可能会如何受到基因变异；以及高通量验证的新方法。在补充年度，我们建议通过侧重于这一领域的更多项目来扩展这项工作，包括锌手指方面的工作蛋白质；遗传变异、RNA表达和GWA之间的联系；最后，高基于CRISPR的吞吐量验证实验。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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.

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)
影响因子：
0
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.

Large-Scale Clonal Analysis Resolves Aging of the Mouse Hematopoietic Stem Cell Compartment.

DOI：
10.1016/j.stem.2018.03.013
发表时间：
2018-04-05
期刊：
Cell stem cell
影响因子：
23.9
作者：
Yamamoto R;Wilkinson AC;Ooehara J;Lan X;Lai CY;Nakauchi Y;Pritchard JK;Nakauchi H
通讯作者：
Nakauchi H

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。