检测由转录因子活性水平介导的eQTL模块。

Detection of eQTL modules mediated by activity levels of transcription factors.

作者信息

Sun Wei, Yu Tianwei, Li Ker-Chau

机构信息

Department of Statistics, University of California at Los Angeles, Los Angeles, California, USA.

出版信息

Bioinformatics. 2007 Sep 1;23(17):2290-7. doi: 10.1093/bioinformatics/btm327. Epub 2007 Jun 28.

DOI:10.1093/bioinformatics/btm327

PMID:17599927

Abstract

MOTIVATION

Studies of gene expression quantitative trait loci (eQTL) in different organisms have shown the existence of eQTL hot spots: each being a small segment of DNA sequence that harbors the eQTL of a large number of genes. Two questions of great interest about eQTL hot spots arise: (1) which gene within the hot spot is responsible for the linkages, i.e. which gene is the quantitative trait gene (QTG)? (2) How does a QTG affect the expression levels of many genes linked to it? Answers to the first question can be offered by available biological evidence or by statistical methods. The second question is harder to address. One simple situation is that the QTG encodes a transcription factor (TF), which regulates the expression of genes linked to it. However, previous results have shown that TFs are not overrepresented in the eQTL hot spots. In this article, we consider the scenario that the propagation of genetic perturbation from a QTG to other linked genes is mediated by the TF activity. We develop a procedure to detect the eQTL modules (eQTL hot spots together with linked genes) that are compatible with this scenario.

RESULTS

We first detect 27 eQTL modules from a yeast eQTL data, and estimate TF activity profiles using the method of Yu and Li (2005). Then likelihood ratio tests (LRTs) are conducted to find 760 relationships supporting the scenario of TF activity mediation: (DNA polymorphism --> cis-linked gene --> TF activity --> downstream linked gene). They are organized into 4 eQTL modules: an amino acid synthesis module featuring a cis-linked gene LEU2 and the mediating TF Leu3; a pheromone response module featuring a cis-linked gene GPA1 and the mediating TF Ste12; an energy-source control module featuring two cis-linked genes, GSY2 and HAP1, and the mediating TF Hap1; a mitotic exit module featuring four cis-linked genes, AMN1, CSH1, DEM1 and TOS1, and the mediating TF complex Ace2/Swi5. Gene Ontology is utilized to reveal interesting functional groups of the downstream genes in each module.

AVAILABILITY

Our methods are implemented in an R package: eqtl.TF, which includes source codes and relevant data. It can be freely downloaded at http://www.stat.ucla.edu/~sunwei/software.htm.

SUPPLEMENTARY INFORMATION

http://www.stat.ucla.edu/~sunwei/yeast_eQTL_TF/supplementary.pdf.

摘要

动机

对不同生物体中的基因表达定量性状位点（eQTL）的研究表明存在eQTL热点：每个热点都是一小段DNA序列，其中包含大量基因的eQTL。关于eQTL热点出现了两个非常有趣的问题：（1）热点内的哪个基因负责这些连锁关系，即哪个基因是数量性状基因（QTG）？（2）一个QTG如何影响与其连锁的许多基因的表达水平？第一个问题的答案可以通过现有的生物学证据或统计方法提供。第二个问题更难解决。一种简单的情况是QTG编码一种转录因子（TF），它调节与其连锁的基因的表达。然而，先前的结果表明TF在eQTL热点中并不占优势。在本文中，我们考虑了遗传扰动从QTG传播到其他连锁基因是由TF活性介导的情况。我们开发了一种程序来检测与这种情况兼容的eQTL模块（eQTL热点以及连锁基因）。

结果

我们首先从酵母eQTL数据中检测到27个eQTL模块，并使用Yu和Li（2005）的方法估计TF活性谱。然后进行似然比检验（LRT）以找到760个支持TF活性介导情况的关系：（DNA多态性→顺式连锁基因→TF活性→下游连锁基因）。它们被组织成4个eQTL模块：一个以顺式连锁基因LEU2和介导TF Leu3为特征的氨基酸合成模块；一个以顺式连锁基因GPA1和介导TF Ste12为特征的信息素反应模块；一个以两个顺式连锁基因GSY2和HAP1以及介导TF Hap1为特征的能源控制模块；一个以四个顺式连锁基因AMN1、CSH1、DEM1和TOS1以及介导TF复合物Ace2/Swi5为特征的有丝分裂退出模块。利用基因本体论揭示每个模块中下游基因的有趣功能组。