Tandem Repeat Sequence Variation as Causative Cis-eQTLs for Protein-Coding Gene Expression Variation: The Case of CSTB
Tandem Repeat Sequence Variation as Causative Cis-eQTLs for Protein-Coding Gene Expression Variation: The Case of CSTB
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DOI：
10.1002/humu.22115
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发表时间：
2012-08-01
期刊：
影响因子：
3.9
通讯作者：
Antonarakis, Stylianos E.
中科院分区：
文献类型：
--
作者：
Borel, Christelle;Migliavacca, Eugenia;Antonarakis, Stylianos E.
关联研究已经揭示了大量基因的表达数量性状位点（eQTLs）。然而，调控基因表达水平的致病变异通常是未知的。我们假设序列重复的拷贝数变化导致了某些基因的表达变化。我们的实验室之前已经发现，CSTB基因启动子区域中c - 174cggggcggggggcg重复序列的罕见扩增导致该基因沉默，从而导致进行性肌阵挛性癫痫。在这里，我们对GenCord收集的173种淋巴母细胞样细胞系（LCLs）和成纤维细胞样本的重复序列长度进行了基因分型，并通过定量实时聚合酶链反应定量测定了CSTB的表达。大多数等位基因包含两个或三个重复的拷贝。独立分析显示，c - 174cggggcggggcg重复序列长度仅在lcl中与CSTB表达密切相关（P = 3.14 X 10-(11)）。对CSTB 2 Mb内基因型和输入单核苷酸多态性（snp）的检测显示，在lcl中，十二聚体重复序列是CSTB最强的顺式eqtl。我们得出结论，常见的2或3拷贝变异可能是CSTB表达变异的致病顺式- eqtl。更广泛地说，我们提出多态性串联重复序列可能代表了基因组中部分顺式等量qtl的致病变异。[j] .农业学报，2012,33:1302-1309。(c) 2012 Wiley期刊有限公司
Association studies have revealed expression quantitative trait loci (eQTLs) for a large number of genes. However, the causative variants that regulate gene expression levels are generally unknown. We hypothesized that copy-number variation of sequence repeats contribute to the expression variation of some genes. Our laboratory has previously identified that the rare expansion of a repeat c.-174CGGGGCGGGGCG in the promoter region of the CSTB gene causes a silencing of the gene, resulting in progressive myoclonus epilepsy. Here, we genotyped the repeat length and quantified CSTB expression by quantitative real-time polymerase chain reaction in 173 lymphoblastoid cell lines (LCLs) and fibroblast samples from the GenCord collection. The majority of alleles contain either two or three copies of this repeat. Independent analysis revealed that the c.-174CGGGGCGGGGCG repeat length is strongly associated with CSTB expression (P = 3.14 X 10-(11)) in LCLs only. Examination of both genotyped and imputed single-nucleotide polymorphisms (SNPs) within 2 Mb of CSTB revealed that the dodecamer repeat represents the strongest cis-eQTL for CSTB in LCLs. We conclude that the common two or three copy variation is likely the causative cis-eQTL for CSTB expression variation. More broadly, we propose that polymorphic tandem repeats may represent the causative variation of a fraction of cis-eQTLs in the genome. Hum Mutat 33:1302-1309, 2012. (c) 2012 Wiley Periodicals, Inc.