Research Institute of Medical Genetics, Tomsk National Research Medical Center, Tomsk, Russian Federation.
Institute of Cytology and Genetics, SB RAS, Novosibirsk, Russian Federation.
Cytogenet Genome Res. 2021;161(3-4):105-119. doi: 10.1159/000514491. Epub 2021 Apr 13.
Most copy number variations (CNVs) in the human genome display incomplete penetrance with unknown underlying mechanisms. One such mechanism may be epigenetic modification, particularly DNA methylation. The IMMP2L gene is located in a critical region for autism susceptibility on chromosome 7q (AUTS1). The level of DNA methylation was assessed by bisulfite sequencing of 87 CpG sites in the IMMP2L gene in 3 families with maternally inherited 7q31.1 microdeletions affecting the IMMP2L gene alone. Bisulfite sequencing revealed comparable levels of DNA methylation in the probands, healthy siblings without microdeletions, and their fathers. In contrast, a reduced DNA methylation index and increased IMMP2L expression were observed in lymphocytes from the healthy mothers compared with the probands. A number of genes were upregulated in the healthy mothers compared to controls and downregulated in probands compared to mothers. These genes were enriched in components of the ribosome and electron transport chain, as well as oxidative phosphorylation and various degenerative conditions. Differential expression in probands and mothers with IMMP2L deletions relative to controls may be due to compensatory processes in healthy mothers with IMMP2L deletions and disturbances of these processes in probands with intellectual disability. The results suggest a possible partial compensation for IMMP2L gene haploinsufficiency in healthy mothers with the 7q31.1 microdeletion by reducing the DNA methylation level. Differential DNA methylation of intragenic CpG sites may affect the phenotypic manifestation of CNVs and explain the incomplete penetrance of chromosomal microdeletions.
大多数人类基因组中的拷贝数变异（CNVs）表现出不完全外显率，其潜在机制尚不清楚。一种可能的机制是表观遗传修饰，特别是 DNA 甲基化。IMMP2L 基因位于染色体 7q（AUTS1）上的自闭症易感性关键区域。通过对 3 个家族中的 87 个 CpG 位点进行亚硫酸氢盐测序，评估了 IMMP2L 基因中的 DNA 甲基化水平，这些家族具有母系遗传的 7q31.1 微缺失，仅影响 IMMP2L 基因。亚硫酸氢盐测序显示，先证者、无微缺失的健康兄弟姐妹及其父亲的 DNA 甲基化水平相当。相比之下，与先证者相比，健康母亲的淋巴细胞中观察到 DNA 甲基化指数降低和 IMMP2L 表达增加。与对照组相比，许多基因在健康母亲中上调，在先证者中下调。这些基因富集于核糖体和电子传递链、氧化磷酸化以及各种退行性疾病的组成成分。与对照组相比，IMMP2L 缺失的先证者和母亲的差异表达可能是由于健康的 IMMP2L 缺失母亲中的代偿过程以及先证者中这些过程的紊乱所致。结果表明，7q31.1 微缺失的健康母亲中可能存在 IMMP2L 基因杂合不足的部分补偿，其机制可能是通过降低 DNA 甲基化水平。内含子 CpG 位点的差异 DNA 甲基化可能会影响 CNVs 的表型表现，并解释染色体微缺失的不完全外显率。
