A Bayesian hierarchical model to detect differentially methylated loci from single nucleotide resolution sequencing data.
A Bayesian hierarchical model to detect differentially methylated loci from single nucleotide resolution sequencing data.
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DOI：
10.1093/nar/gku154
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发表时间：
2014-04
影响因子：
14.9
通讯作者：
Wu H
中科院分区：
文献类型：
--
作者：
Feng H;Conneely KN;Wu H
DNA甲基化是一种重要的表观遗传修饰，在包括基因调控、发育和疾病在内的细胞过程中发挥重要作用，并且在大多数类型的癌症中广泛失调。测序技术的最新进展使得能够通过诸如全基因组亚硫酸氢盐测序和减少代表性亚硫酸氢盐测序的方法以单核苷酸分辨率测量DNA甲基化。在DNA甲基化研究中，一项关键任务是确定不同生物学背景下的差异，例如肿瘤和正常组织之间的差异。测序研究中的一个挑战是生物学重复的数量通常受到测序成本的限制。重复次数少导致方差估计不稳定，这会降低检测差异甲基化基因座（DML）的准确性。在这里，我们提出了一种新的统计方法来检测DML时，比较两个治疗组。测序计数通过对数正态-β-二项式分层模型描述，其为不同CpG位点之间的信息共享提供了基础。开发Wald检验用于每个CpG位点的假设检验。仿真结果表明，所提出的方法产生了改进的DML检测相比，现有的方法，特别是当重复数低。所提出的方法在Bioconductor包DSS中实现。
DNA methylation is an important epigenetic modification that has essential roles in cellular processes including gene regulation, development and disease and is widely dysregulated in most types of cancer. Recent advances in sequencing technology have enabled the measurement of DNA methylation at single nucleotide resolution through methods such as whole-genome bisulfite sequencing and reduced representation bisulfite sequencing. In DNA methylation studies, a key task is to identify differences under distinct biological contexts, for example, between tumor and normal tissue. A challenge in sequencing studies is that the number of biological replicates is often limited by the costs of sequencing. The small number of replicates leads to unstable variance estimation, which can reduce accuracy to detect differentially methylated loci (DML). Here we propose a novel statistical method to detect DML when comparing two treatment groups. The sequencing counts are described by a lognormal-beta-binomial hierarchical model, which provides a basis for information sharing across different CpG sites. A Wald test is developed for hypothesis testing at each CpG site. Simulation results show that the proposed method yields improved DML detection compared to existing methods, particularly when the number of replicates is low. The proposed method is implemented in the Bioconductor package DSS.
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