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一种用于在真核生物启动子区域进行计算机模拟发现具有统计学意义的顺式调控元件的新型成对比较方法:应用于拟南芥。

A novel pairwise comparison method for in silico discovery of statistically significant cis-regulatory elements in eukaryotic promoter regions: application to Arabidopsis.

作者信息

Shamloo-Dashtpagerdi Roohollah, Razi Hooman, Aliakbari Massumeh, Lindlöf Angelica, Ebrahimi Mahdi, Ebrahimie Esmaeil

机构信息

Department of Crop Production and Plant Breeding, College of Agriculture, Shiraz University, Shiraz, Iran.

Department of Crop Production and Plant Breeding, College of Agriculture, Shiraz University, Shiraz, Iran.

出版信息

J Theor Biol. 2015 Jan 7;364:364-76. doi: 10.1016/j.jtbi.2014.09.038. Epub 2014 Oct 7.

Abstract

Cis regulatory elements (CREs), located within promoter regions, play a significant role in the blueprint for transcriptional regulation of genes. There is a growing interest to study the combinatorial nature of CREs including presence or absence of CREs, the number of occurrences of each CRE, as well as of their order and location relative to their target genes. Comparative promoter analysis has been shown to be a reliable strategy to test the significance of each component of promoter architecture. However, it remains unclear what level of difference in the number of occurrences of each CRE is of statistical significance in order to explain different expression patterns of two genes. In this study, we present a novel statistical approach for pairwise comparison of promoters of Arabidopsis genes in the context of number of occurrences of each CRE within the promoters. First, using the sample of 1000 Arabidopsis promoters, the results of the goodness of fit test and non-parametric analysis revealed that the number of occurrences of CREs in a promoter sequence is Poisson distributed. As a promoter sequence contained functional and non-functional CREs, we addressed the issue of the statistical distribution of functional CREs by analyzing the ChIP-seq datasets. The results showed that the number of occurrences of functional CREs over the genomic regions was determined as being Poisson distributed. In accordance with the obtained distribution of CREs occurrences, we suggested the Audic and Claverie (AC) test to compare two promoters based on the number of occurrences for the CREs. Superiority of the AC test over Chi-square (2×2) and Fisher's exact tests was also shown, as the AC test was able to detect a higher number of significant CREs. The two case studies on the Arabidopsis genes were performed in order to biologically verify the pairwise test for promoter comparison. Consequently, a number of CREs with significantly different occurrences was identified between the promoters. The results of the pairwise comparative analysis together with the expression data for the studied genes revealed the biological significance of the identified CREs.

摘要

位于启动子区域内的顺式调控元件(CREs)在基因转录调控蓝图中发挥着重要作用。人们对研究CREs的组合性质的兴趣日益浓厚,这包括CREs的存在与否、每个CRE的出现次数,以及它们相对于靶基因的顺序和位置。比较启动子分析已被证明是检验启动子结构各组成部分重要性的可靠策略。然而,尚不清楚每个CRE出现次数的差异达到何种程度才具有统计学意义,以便解释两个基因的不同表达模式。在本研究中,我们提出了一种新颖的统计方法,用于在启动子内每个CRE出现次数的背景下对拟南芥基因的启动子进行成对比较。首先,使用1000个拟南芥启动子的样本,拟合优度检验和非参数分析的结果表明,启动子序列中CREs的出现次数呈泊松分布。由于启动子序列包含功能性和非功能性CREs,我们通过分析ChIP-seq数据集解决了功能性CREs的统计分布问题。结果表明,基因组区域上功能性CREs的出现次数被确定为呈泊松分布。根据获得的CREs出现次数分布,我们建议使用奥迪克和克拉弗里(AC)检验,基于CREs的出现次数来比较两个启动子。还显示了AC检验相对于卡方(2×2)检验和费舍尔精确检验的优越性,因为AC检验能够检测到更多具有显著意义的CREs。为了从生物学上验证用于启动子比较的成对检验,对拟南芥基因进行了两个案例研究。因此,在启动子之间鉴定出了一些出现次数有显著差异的CREs。成对比较分析的结果与所研究基因的表达数据一起揭示了所鉴定的CREs的生物学意义。

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