Exploring the selective vulnerability in Alzheimer disease using tissue specific variant analysis
Exploring the selective vulnerability in Alzheimer disease using tissue specific variant analysis
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DOI：
10.1016/j.ygeno.2018.05.024
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发表时间：
2019-07-01
期刊：
影响因子：
4.4
通讯作者：
Gromiha, M. Michael
中科院分区：
文献类型：
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作者：
Dharshini, S. Akila Parvathy;Taguchi, Y-H;Gromiha, M. Michael
大脑不同区域的选择性脆弱性是神经退行性疾病的关键因素。阿尔茨海默病（Alzheimer's disease，AD）是一种严重损害内侧颞叶海马神经元的疾病。识别组织特异性变体对于感知AD中的选择性脆弱性至关重要。在目前的工作中，我们将mRNA-seq数据与HG 19/HG 38基因组组装进行了比对，并使用序列比对图工具鉴定了AD颞叶、额叶和其他叶中存在的特定变异。我们将结果与各种神经系统疾病的全基因组关联和基因表达数量性状位点研究进行了比较。我们还通过RNA修饰数据库区分了变体和表位转录组修饰，并评估了编码/UTR区的变体效应。此外，我们开发了遗传和功能相互作用网络，以了解预测的脆弱变异和差异表达基因之间的关系。我们发现颞叶中参与胶质细胞生成、中间纤维组织的基因发生了改变。氧化磷酸化和钙离子稳态在额叶被改变，蛋白质降解和凋亡信号在其他脑叶被改变。从这项研究中，我们提出，神经胶质细胞结构完整性的破坏，有缺陷的胶质细胞，和失败的胶质神经元通信是选择性脆弱性的主要因素。
The selective vulnerability of distinct regions of the brain is a critical factor in neurodegenerative disorders. In Alzheimer's disease (AD), neurons in hippocampus situated in medial temporal lobe are immensely damaged. Identifying tissue-specific variants is essential in order to perceive the selective vulnerability in AD. In current work, we aligned mRNA-seq data with HG19/HG38 genomic assembly and identified specific variations present in temporal, frontal and other lobes of the AD using sequence alignment map tools. We compared the results with the genome-wide association and gene expression quantitative trait loci studies of the various neurological disorders. We also distinguished variants and epitranscriptomic modifications through the RNA-modification database and evaluated the variant effect in the coding/UTR regions. In addition, we developed genetic and functional interaction networks to understand the relationship between predicted vulnerable variations and differentially expressed genes. We found that genes involved in gliogenesis, intermediate filament organization are altered in the temporal lobe. Oxidative phosphorylation, and calcium ion homeostasis are modified in the frontal lobe, and protein degradation, apoptotic signaling are altered in other lobes. From this study, we propose that disruption of glial cell structural integrity, defective gliogenesis, and failure in glia-neuron communication are the primary factors for selective vulnerability.