Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
PLoS One. 2013 Sep 4;8(9):e67752. doi: 10.1371/journal.pone.0067752. eCollection 2013.
Although historically considered as junk-DNA, tandemly repeated sequence motifs can affect human phenotype. For example, variable number tandem repeats (VNTR) with embedded enhancers have been shown to regulate gene transcription. The post-zygotic variation is the presence of genetically distinct populations of cells in an individual derived from a single zygote, and this is an understudied aspect of genome biology. We report somatically variable VNTR with sequence properties of an enhancer, located upstream of IFNAR1. Initially, SNP genotyping of 63 monozygotic twin pairs and multiple tissues from 21 breast cancer patients suggested a frequent post-zygotic mosaicism. The VNTR displayed a repeated 32 bp core motif in the center of the repeat, which was flanked by similar variable motifs. A total of 14 alleles were characterized based on combinations of segments, which showed post-zygotic and inter-individual variation, with up to 6 alleles in a single subject. Somatic variation occurred in ∼24% of cases. In this hypervariable region, we found a clustering of transcription factor binding sites with strongest sequence similarity to mouse Foxg1 transcription factor binding motif. This study describes a VNTR with sequence properties of an enhancer that displays post-zygotic and inter-individual genetic variation. This element is within a locus containing four related cytokine receptors: IFNAR2, IL10Rβ, IFNAR1 and IFNGR2, and we hypothesize that it might function in transcriptional regulation of several genes in this cluster. Our findings add another level of complexity to the variation among VNTR-based enhancers. Further work may unveil the normal function of this VNTR in transcriptional control and its possible involvement in diseases connected with these receptors, such as autoimmune conditions and cancer.
虽然串联重复序列基序在历史上被认为是“垃圾 DNA”，但它们可以影响人类表型。例如，具有嵌入式增强子的可变数目串联重复（VNTR）已被证明可以调节基因转录。合子后变异是指个体中存在来自单个合子的遗传上不同的细胞群体，这是基因组生物学中一个研究不足的方面。我们报告了位于 IFNAR1 上游的具有增强子序列特性的体细胞可变 VNTR。最初，对 63 对同卵双胞胎和 21 名乳腺癌患者的多个组织进行 SNP 基因分型表明，合子后镶嵌现象频繁发生。VNTR 在重复的中心显示出 32 bp 的重复核心基序，其两侧是类似的可变基序。总共根据片段组合表征了 14 个等位基因，这些等位基因显示出合子后和个体间的变异，在单个受试者中多达 6 个等位基因。体细胞变异发生在约 24%的病例中。在这个高变区域，我们发现转录因子结合位点聚类与小鼠 Foxg1 转录因子结合基序具有最强的序列相似性。这项研究描述了一种具有增强子序列特性的 VNTR，它表现出合子后和个体间的遗传变异。这个元件位于包含四个相关细胞因子受体的基因座内：IFNAR2、IL10Rβ、IFNAR1 和 IFNGR2，我们假设它可能在这个基因簇中几个基因的转录调控中发挥作用。我们的发现为基于 VNTR 的增强子的变异增加了另一个层次的复杂性。进一步的研究可能会揭示这个 VNTR 在转录控制中的正常功能及其在与这些受体相关的疾病（如自身免疫性疾病和癌症）中的可能参与。
