冰岛大学Kari Stefansson课题组发现，CpG甲基化与基因表达之间的相关性是由序列变异驱动的。相关论文于2024年7月24日发表在《自然—遗传学》杂志上。

研究人员使用纳米孔测序技术检测了7,179个全血基因组中1,530万个CpG位点的单倍型特异性甲基化率。研究发现了189,178个甲基化耗竭序列，其中至少有一个单倍型的三个或更多近端CpGs未甲基化。共有77,789个甲基化缺失序列（约占41%）与80,503个顺式作用序列变异相关，研究人员称之为等位基因特异性甲基化定量性状位点（ASM-QTLs）。

对用于进行纳米孔测序的相同抽血样本中的896份样本进行的RNA测序显示，ASM-QTL（即DNA序列变异）大部分诱导产生了基因表达与CpG甲基化之间的相关性。在与血液学特征相关的序列变异中，ASM-QTL富集了40.2倍（95%置信区间为32.2-49.9），这表明ASM-QTL是非编码基因组中的重要功能单元。

据介绍，转录因子结合基因的启动子和增强子序列，并缺少甲基化CpG位点（在DNA中胞嘧啶位于鸟嘌呤之前）。这些序列中甲基化CpGs的缺失通常与基因表达增加有关，这表明甲基化具有调控作用。

附：英文原文

Title: The correlation between CpG methylation and gene expression is driven by sequence variants

Author: Stefansson, Olafur Andri, Sigurpalsdottir, Brynja Dogg, Rognvaldsson, Solvi, Halldorsson, Gisli Hreinn, Juliusson, Kristinn, Sveinbjornsson, Gardar, Gunnarsson, Bjarni, Beyter, Doruk, Jonsson, Hakon, Gudjonsson, Sigurjon Axel, Olafsdottir, Thorunn Asta, Saevarsdottir, Saedis, Magnusson, Magnus Karl, Lund, Sigrun Helga, Tragante, Vinicius, Oddsson, Asmundur, Hardarson, Marteinn Thor, Eggertsson, Hannes Petur, Gudmundsson, Reynir L., Sverrisson, Sverrir, Frigge, Michael L., Zink, Florian, Holm, Hilma, Stefansson, Hreinn, Rafnar, Thorunn, Jonsdottir, Ingileif, Sulem, Patrick, Helgason, Agnar, Gudbjartsson, Daniel F., Halldorsson, Bjarni V., Thorsteinsdottir, Unnur, Stefansson, Kari

Issue&Volume: 2024-07-24

Abstract: Gene promoter and enhancer sequences are bound by transcription factors and are depleted of methylated CpG sites (cytosines preceding guanines in DNA). The absence of methylated CpGs in these sequences typically correlates with increased gene expression, indicating a regulatory role for methylation. We used nanopore sequencing to determine haplotype-specific methylation rates of 15.3million CpG units in 7,179 whole-blood genomes. We identified 189,178 methylation depleted sequences where three or more proximal CpGs were unmethylated on at least one haplotype. A total of 77,789 methylation depleted sequences (~41%) associated with 80,503 cis-acting sequence variants, which we termed allele-specific methylation quantitative trait loci (ASM-QTLs). RNA sequencing of 896 samples from the same blood draws used to perform nanopore sequencing showed that the ASM-QTL, that is, DNA sequence variability, drives most of the correlation found between gene expression and CpG methylation. ASM-QTLs were enriched 40.2-fold (95% confidence interval 32.2, 49.9) among sequence variants associating with hematological traits, demonstrating that ASM-QTLs are important functional units in the noncoding genome.

DOI: 10.1038/s41588-024-01851-2

Source: https://www.nature.com/articles/s41588-024-01851-2