基于病例对照组的检验差异甲基化基因功能区域的方法  

A Statistical Method for Detecting Differentially Methylated Gene Functional Regions Based on Case-Control Studies

作　　者：马欣宇 王婵 胡跃清 

机构地区：[1]复旦大学生命科学学院生物统计学与计算生物学系,上海200433

出　　处：《复旦学报（自然科学版）》2017年第6期701-711,共11页Journal of Fudan University：Natural Science

基　　金：国家自然科学基金(11571082;11171075)

摘　　要：DNA甲基化是一种重要的表观遗传学修饰,能够参与基因表达调控从而影响生理活动.在病例-对照组研究中,利用甲基化水平定位与疾病相关联的基因功能区域,有助于了解甲基化调控基因表达的机制,为后续研究提供疾病关联基因的线索.目前检验甲基化差异区域的方法存在一定不足:一是缺乏定义差异甲基化区域的统一标准;二是检测结果存在横跨多个基因功能区域的现象,难以进行生物学解释.本文基于得分检验(Zscore test)提出了以基因功能区域为单位的检验差异甲基化水平的方法cZST.该方法的特点是依靠位点物理距离和染色体全局信息修正协方差矩阵.模拟研究表明cZST在亚硫酸氢盐测序数据样本量小、读数低、扰动位点多的情形下具有高功效,且优于现有方法.将cZST运用到乳腺导管癌真实数据中,检测出与疾病显著相关的661个基因功能区和81个单位点.基因注释分析说明了cZST方法的有效性,并发现Dbl、Pleckstrin基因家族及Rho调控基因的甲基化与乳腺导管癌紧密相关,为后续研究提供指引.DNA methylation is an important epigenetic modification that participates in the regulation of gene expression and other biological activities.In case-control studies,searching for differentially methylated gene functional regions associated with disease can provide clues of disease-related gene list for follow-up studies.Nowadays existing differential methylation detection methods are lack of a uniform standard for defining differentially methylated regions.Also test results can be across multiple genes or multiple functional regions,bringing difficulty for biological interpretation.In this paper,a statistical approach,cZST,is proposed based on Zscore test.It is able to detect differences of methylation levels in each gene functional region.This method uses physical distances between sites and the global information of methylation levels in each chromosome to modify the covariance matrix.The simulation results show that cZST is superior to other methods in BS-seq data of a small sample size or a low reading depth.In the real data analysis of a breast ductal cancer study,661 significant functional regions and 81 significant single loci are recognized.Gene annotation analysis of results demonstrates the effectiveness of cZST.Also we find that in regulator genes of Rho,Dbl and Pleckstrin gene families,DNA methylation level differences are associated with breast ductal carcinoma affection.

关 键 词：差异甲基化检验 亚硫酸氢盐测序 功能富集分析 

分 类 号：Q348[生物学—遗传学]