Using three-dimensional genome structure to refine eQTL detection

利用三维基因组结构完善eQTL检测

• 批准号: 10356618
• 负责人: Jinrui Xu
• 金额: $ 33.5万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-22 至 2023-08-13
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10356618
• 关键词: 3-Dimensional; Base Pairing; Biological; Biological Assay; Bypass; Cells; Chromatin Interaction Analysis by Paired-End Tag Sequencing; Chromosomes; Data; Data Set; Databases; Detection; Development; Distal; Enhancers; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Genome; Genomic Segment; Genotype; Genotype-Tissue Expression Project; Gold; Hi-C; Human; Human Herpesvirus 4; In Situ; Lymphocyte; Medical; Noise; Paper; Performance; Procedures; Publications; Publishing; Quantitative Trait Loci; Regulatory Element; Sampling; Source Code; Structure; Testing; Tissues; Transcription Initiation Site; Variant; base; cell type; computational pipelines; genetic variant; genomic locus; histone modification; human disease; improved; insight; programs; promoter; transforming virus

SUMMARY The Genotype-Tissue Expression (GTEx) Program studies the impact of genetic variants on gene expression in many human cell types and tissues. To identify the expression quantitative trait loci (eQTLs) of each gene, the genetic variants within one million base pairs (1 Mb) of the transcription start site (TSS) of the gene are considered as the candidates, and then the GTEx computational pipeline identifies the significant candidates as eQTLs of the gene. This 1 Mb threshold is being widely used as the gold standard in the field to reduce multiple tests. Using this threshold assumes that genetic variants outside of this distance contribute little to gene expression, and thus are unlikely to be eQTLs. However, we observed that, on average, 10% of cis-regulatory elements (CREs) are outside of the 1 Mb threshold, herein referred to as distal CREs. Therefore, the eQTLs in such CREs are missed using the 1 Mb threshold. In addition, the 1 Mb threshold implicitly assumes that the majority of genomic regions within the distance to a TSS are CREs that regulate the gene. However, we found that on average CREs account for only 2.1% of the ±1Mb regions around a TSS. Moreover, it is not uncommon that CREs skip the closest genes to regulate distal genes. These observations indicate that many candidate variants within the 1 Mb distance may be noise, and thus impede the detection of bona fide eQTLs. In line with this, we found that using distance thresholds smaller than 1 Mb substantially increase the numbers of eQTLs and associated genes. These results together indicate that the current eQTLs detection can be improved by focusing only on the CREs of genes. To this end, we will use the genome structure data from 4D Nucleome and other public data to build CRE-gene linkages. These linkages are expected to detect more eQTLs, especially the weak ones. The results will enhance the existing GTEx dataset and substantially improve our understanding of gene expression regulation and human diseases.

总结 基因型-组织表达（GTEx）计划研究遗传变异的影响 在许多人类细胞类型和组织中的基因表达。来标识表达式 每个基因的数量性状位点（eQTL），在一百万个碱基对（1 将该基因的转录起始位点（TSS）的10个核苷酸（Mb）作为候选，然后 GTEx计算流水线将显著候选者鉴定为基因的eQTL。这 1 Mb阈值被广泛用作该领域的黄金标准，以减少多次测试。 使用这个阈值假设在这个距离之外的遗传变异对 基因表达，因此不太可能是eQTL。然而，我们观察到，平均而言， 10%的顺式调节元件（CRE）在1Mb阈值之外，在本文中称为 远端CREs。因此，使用1Mb阈值会遗漏这些CRE中的eQTL。在 此外，1Mb阈值隐含地假设了在基因组区域内的大多数基因组区域都是不稳定的。 与TSS距离较远的是调节该基因的CREs。然而，我们发现， 仅占TSS周围± 1Mb区域的2.1%。此外，以下情况并不罕见： CREs跳过最近的基因来调节远端基因。这些观察表明，许多 在IMb距离内的候选变体可能是噪声，并且因此阻碍了对候选变体的检测。 真正的eQTL。与此一致，我们发现使用小于1 Mb的距离阈值 显著增加eQTL和相关基因的数量。这些结果一起 表明当前eQTL检测可以通过仅关注以下基因的CRE来改进： 基因.为此，我们将使用来自4D Nucleome和其他公共的基因组结构数据， 数据来建立CRE-gene连接。这些连锁有望检测到更多的eQTL， 尤其是那些弱者结果将增强现有的GTEx数据集， 提高我们对基因表达调控和人类疾病的理解。