Illumina DNA methylation microarrays enable epigenome-wide analysis vastly used for the discovery of novel DNA methylation variation in health and disease. However, the microarrays’ probe design cannot fully consider the vast human genetic diversity, leading to genetic artifacts. Distinguishing genuine from artifactual genetic influence is of particular relevance in the study of DNA methylation heritability and methylation quantitative trait loci. But despite its importance, current strategies to account for genetic artifacts are lagging due to a limited mechanistic understanding on how such artifacts operate. To address this, we develop and benchmark UMtools, an R-package containing novel methods for the quantification and qualification of genetic artifacts based on fluorescence intensity signals. With our approach, we model and validate known SNPs/indels on a genetically controlled dataset of monozygotic twins, and we estimate minor allele frequency from DNA methylation data and empirically detect variants not included in dbSNP. Moreover, we identify examples where genetic artifacts interact with each other or with imprinting, X-inactivation, or tissue-specific regulation. Finally, we propose a novel strategy based on co-methylation that can discern between genetic artifacts and genuine genomic influence. We provide an atlas to navigate through the huge diversity of genetic artifacts encountered on DNA methylation microarrays. Overall, our study sets the ground for a paradigm shift in the study of the genetic component of epigenetic variation in DNA methylation microarrays.

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重新审视 DNA 甲基化微阵列上的遗传产物揭示了新的生物学意义

Illumina DNA 甲基化微阵列可实现表观基因组范围内的分析，广泛用于发现健康和疾病中的新型 DNA 甲基化变异。然而，微阵列的探针设计无法充分考虑人类巨大的遗传多样性，导致遗传伪影。在 DNA 甲基化遗传力和甲基化数量性状位点的研究中，区分真实的和人为的遗传影响尤其重要。尽管它很重要，但由于对遗传伪影如何运作的机械理解有限，目前解释遗传伪影的策略仍然滞后。为了解决这个问题，我们开发了 UMtools 并对其进行了基准测试，这是一个 R 软件包，包含基于荧光强度信号对遗传伪影进行量化和鉴定的新方法。通过我们的方法，我们在同卵双胞胎的遗传控制数据集上对已知的 SNP/插入缺失进行建模和验证，并根据 DNA 甲基化数据估计次要等位基因频率，并凭经验检测 dbSNP 中未包含的变异。此外，我们还发现了遗传伪影彼此相互作用或与印记、X 失活或组织特异性调节相互作用的例子。最后，我们提出了一种基于共甲基化的新策略，可以区分遗传伪影和真正的基因组影响。我们提供了一个图谱来导航 DNA 甲基化微阵列上遇到的巨大多样性的遗传产物。总的来说，我们的研究为 DNA 甲基化微阵列表观遗传变异的遗传成分研究的范式转变奠定了基础。