He Yijie, Huang Lin, Tang Yaqin, Yang Zeyuan, Han Zhijie
Department of Bioinformatics, School of Basic Medicine, Chongqing Medical University, Chongqing, China.
Front Genet. 2021 Nov 12;12:769804. doi: 10.3389/fgene.2021.769804. eCollection 2021.
Multiple sclerosis (MS) is an autoimmune disease characterized by inflammatory demyelinating lesions in the central nervous system. Recently, the dysregulation of alternative splicing (AS) in the brain has been found to significantly influence the progression of MS. Moreover, previous studies demonstrate that many MS-related variants in the genome act as the important regulation factors of AS events and contribute to the pathogenesis of MS. However, by far, no genome-wide research about the effect of genomic variants on AS events in MS has been reported. Here, we first implemented a strategy to obtain genomic variant genotype and AS isoform average percentage spliced-in values from RNA-seq data of 142 individuals (51 MS patients and 91 controls). Then, combing the two sets of data, we performed a -splicing quantitative trait loci (sQTLs) analysis to identify the -acting loci and the affected differential AS events in MS and further explored the characteristics of these -sQTLs. Finally, the weighted gene coexpression network and gene set enrichment analyses were used to investigate gene interaction pattern and functions of the affected AS events in MS. In total, we identified 5835 variants affecting 672 differential AS events. The -sQTLs tend to be distributed in proximity of the gene transcription initiation site, and the intronic variants of them are more capable of regulating AS events. The retained intron AS events are more susceptible to influence of genome variants, and their functions are involved in protein kinase and phosphorylation modification. In summary, these findings provide an insight into the mechanism of MS.
多发性硬化症（MS）是一种自身免疫性疾病，其特征是中枢神经系统出现炎性脱髓鞘病变。最近，人们发现大脑中可变剪接（AS）的失调会显著影响MS的进展。此外，先前的研究表明，基因组中许多与MS相关的变异作为AS事件的重要调控因子，参与了MS的发病机制。然而，到目前为止，尚未有关于基因组变异对MS中AS事件影响的全基因组研究报道。在此，我们首先实施了一种策略，从142名个体（51名MS患者和91名对照）的RNA测序数据中获取基因组变异基因型和AS异构体平均剪接入值。然后，将这两组数据相结合，我们进行了剪接定量性状位点（sQTLs）分析，以识别MS中的顺式作用位点和受影响的差异AS事件，并进一步探索这些sQTLs的特征。最后，使用加权基因共表达网络和基因集富集分析来研究MS中受影响的AS事件的基因相互作用模式和功能。我们总共鉴定出5835个影响672个差异AS事件的变异。sQTLs倾向于分布在基因转录起始位点附近，其中的内含子变异更能够调控AS事件。保留内含子的AS事件更容易受到基因组变异的影响，其功能涉及蛋白激酶和磷酸化修饰。总之，这些发现为MS的发病机制提供了深入见解。
