Center for Epigenetics, Van Andel Research Institute, 333 Bostwick Ave., N.E., Grand Rapids, MI 49503 USA.
Nucleic Acids Res. 2018 Nov 16;46(20):e123. doi: 10.1093/nar/gky691.
We report a new class of artifacts in DNA methylation measurements from Illumina HumanMethylation450 and MethylationEPIC arrays. These artifacts reflect failed hybridization to target DNA, often due to germline or somatic deletions and manifest as incorrectly reported intermediate methylation. The artifacts often survive existing preprocessing pipelines, masquerade as epigenetic alterations and can confound discoveries in epigenome-wide association studies and studies of methylation-quantitative trait loci. We implement a solution, P-value with out-of-band (OOB) array hybridization (pOOBAH), in the R package SeSAMe. Our method effectively masks deleted and hyperpolymorphic regions, reducing or eliminating spurious reports of epigenetic silencing at oft-deleted tumor suppressor genes such as CDKN2A and RB1 in cases with somatic deletions. Furthermore, our method substantially decreases technical variation whilst retaining biological variation, both within and across HM450 and EPIC platform measurements. SeSAMe provides a light-weight, modular DNA methylation data analysis suite, with a performant implementation suitable for efficient analysis of thousands of samples.
我们报告了一类新的 DNA 甲基化测量伪影，这些伪影来自于 Illumina HumanMethylation450 和 MethylationEPIC 芯片。这些伪影反映了靶向 DNA 杂交失败，通常是由于种系或体细胞缺失，并表现为错误报告的中间甲基化。这些伪影经常在现有的预处理管道中幸存下来，伪装成表观遗传改变，并可能混淆全基因组关联研究和甲基化数量性状基因座研究中的发现。我们在 R 包 SeSAMe 中实现了一种解决方案，即带外（OOB）阵列杂交的 p 值（pOOBAH）。我们的方法有效地屏蔽了缺失和高度多态性区域，减少或消除了在存在体细胞缺失的情况下，经常缺失的肿瘤抑制基因（如 CDKN2A 和 RB1）中表观遗传沉默的虚假报告。此外，我们的方法在保留生物变异的同时，大大降低了技术变异，无论是在 HM450 还是 EPIC 平台测量内还是之间。SeSAMe 提供了一个轻量级、模块化的 DNA 甲基化数据分析套件，具有高性能的实现，适合于对数千个样本进行高效分析。
