Halla-Aho Viivi, Lähdesmäki Harri
Department of Computer Science, Aalto University, FI-00076 Aalto, Finland.
Bioinformatics. 2020 Nov 1;36(17):4535-4543. doi: 10.1093/bioinformatics/btaa539.
DNA methylation is an important epigenetic modification, which has multiple functions. DNA methylation and its connections to diseases have been extensively studied in recent years. It is known that DNA methylation levels of neighboring cytosines are correlated and that differential DNA methylation typically occurs rather as regions instead of individual cytosine level.
We have developed a generalized linear mixed model, LuxUS, that makes use of the correlation between neighboring cytosines to facilitate analysis of differential methylation. LuxUS implements a likelihood model for bisulfite sequencing data that accounts for experimental variation in underlying biochemistry. LuxUS can model both binary and continuous covariates, and mixed model formulation enables including replicate and cytosine random effects. Spatial correlation is included to the model through a cytosine random effect correlation structure. We show with simulation experiments that using the spatial correlation, we gain more power to the statistical testing of differential DNA methylation. Results with real bisulfite sequencing dataset show that LuxUS is able to detect biologically significant differentially methylated cytosines.
The tool is available at https://github.com/hallav/LuxUS.
Supplementary data are available at Bioinformatics online.
DNA甲基化是一种重要的表观遗传修饰，具有多种功能。近年来，DNA甲基化及其与疾病的关联已得到广泛研究。已知相邻胞嘧啶的DNA甲基化水平是相关的，并且差异DNA甲基化通常以区域形式出现，而非单个胞嘧啶水平。
我们开发了一种广义线性混合模型LuxUS，该模型利用相邻胞嘧啶之间的相关性来促进差异甲基化分析。LuxUS为亚硫酸氢盐测序数据实现了一个似然模型，该模型考虑了基础生物化学中的实验变异。LuxUS可以对二元和连续协变量进行建模，并且混合模型公式允许纳入重复和胞嘧啶随机效应。通过胞嘧啶随机效应相关结构将空间相关性纳入模型。我们通过模拟实验表明，利用空间相关性，我们在差异DNA甲基化的统计检验中获得了更大的功效。真实亚硫酸氢盐测序数据集的结果表明，LuxUS能够检测到具有生物学意义的差异甲基化胞嘧啶。
该工具可在https://github.com/hallav/LuxUS获取。
补充数据可在《生物信息学》在线获取。
