Identifying unstable CNG repeat loci in the human genome: a heuristic approach and implications for neurological disorders.

IF 1 Q4 GENETICS & HEREDITY
Varun Suroliya, Bharathram Uppili, Manish Kumar, Vineet Jha, Achal K Srivastava, Mohammed Faruq
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Abstract

Tandem nucleotide repeat (TNR) expansions, particularly the CNG nucleotide configuration, are associated with a variety of neurodegenerative disorders. In this study, we aimed to identify novel unstable CNG repeat loci associated with the neurogenetic disorder spinocerebellar ataxia (SCA). Using a computational approach, 15,069 CNG repeat loci in the coding and noncoding regions of the human genome were identified. Based on the feature selection criteria (repeat length >10 and functional location of repeats), we selected 52 repeats for further analysis and evaluated the repeat length variability in 100 control subjects. A subset of 19 CNG loci observed to be highly variable in control subjects was selected for subsequent analysis in 100 individuals with SCA. The genes with these highly variable repeats also exhibited higher gene expression levels in the brain according to the tissue expression dataset (GTEx). No pathogenic expansion events were identified in patient samples, which is a limitation given the size of the patient group examined; however, these loci contain potential risk alleles for expandability. Recent studies have implicated GLS, RAI1, GIPC1, MED15, EP400, MEF2A, and CNKSR2 in neurological diseases, with GLS, GIPC1, MED15, RAI1, and MEF2A sharing the same repeat loci reported in this study. This finding validates the approach of evaluating repeat loci in different populations and their possible implications for human pathologies.

Abstract Image

识别人类基因组中不稳定的 CNG 重复位点:启发式方法及其对神经系统疾病的影响。
串联核苷酸重复(TNR)扩增,尤其是 CNG 核苷酸构型,与多种神经退行性疾病有关。在这项研究中,我们旨在确定与神经遗传性疾病脊髓小脑共济失调(SCA)相关的新型不稳定 CNG 重复位点。通过计算方法,我们确定了人类基因组编码区和非编码区中的 15,069 个 CNG 重复位点。根据特征选择标准(重复长度大于 10 和重复的功能位置),我们选择了 52 个重复位点进行进一步分析,并评估了 100 名对照受试者的重复长度变异性。在对照受试者中观察到的 19 个 CNG 基因位点的高变异性子集被选中,用于对 100 名 SCA 患者进行后续分析。根据组织表达数据集(GTEx),这些重复序列高度可变的基因在大脑中也表现出较高的基因表达水平。在患者样本中未发现致病性扩增事件,这与所研究的患者群体规模有关;不过,这些基因位点包含潜在的扩增风险等位基因。最近的研究表明,GLS、RAI1、GIPC1、MED15、EP400、MEF2A 和 CNKSR2 与神经系统疾病有关,其中 GLS、GIPC1、MED15、RAI1 和 MEF2A 与本研究中报告的重复位点相同。这一发现验证了在不同人群中评估重复位点的方法及其对人类病症的可能影响。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Human Genome Variation
Human Genome Variation Biochemistry, Genetics and Molecular Biology-Genetics
CiteScore
2.30
自引率
0.00%
发文量
39
审稿时长
13 weeks
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