Erasmus MC, University Medical Center Rotterdam, Department of Genetic Identification, Rotterdam, the Netherlands.
Genome Biol. 2021 Sep 21;22(1):274. doi: 10.1186/s13059-021-02484-y.
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.
Illumina DNA 甲基化微阵列可实现全基因组范围内的表观基因组分析，广泛用于在健康和疾病中发现新的 DNA 甲基化变异。然而，微阵列的探针设计不能完全考虑到广泛的人类遗传多样性，从而导致遗传伪影。区分真正的遗传影响和人为的遗传影响对于研究 DNA 甲基化遗传力和甲基化数量性状基因座尤为重要。但是，尽管这很重要，但由于对这些伪影如何运作的机制理解有限，目前用于解释遗传伪影的策略仍存在滞后。
为了解决这个问题，我们开发并基准测试了 UMtools，这是一个包含基于荧光强度信号的遗传伪影定量和定性的新方法的 R 包。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/indels 进行建模和验证，并从 DNA 甲基化数据中估计次要等位基因频率，并通过经验检测未包含在 dbSNP 中的变体。此外，我们还发现了遗传伪影与印迹、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，用于在 DNA 甲基化微阵列上遇到的大量遗传伪影中进行导航。总的来说，我们的研究为在 DNA 甲基化微阵列中研究表观遗传变异的遗传成分方面的范式转变奠定了基础。
