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Genome-wide Identification and Analysis of Splicing QTLs in Multiple Sclerosis by RNA-Seq Data

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 demons...

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Autores principales: He, Yijie, Huang, Lin, Tang, Yaqin, Yang, Zeyuan, Han, Zhijie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8633104/
https://www.ncbi.nlm.nih.gov/pubmed/34868258
http://dx.doi.org/10.3389/fgene.2021.769804
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author He, Yijie
Huang, Lin
Tang, Yaqin
Yang, Zeyuan
Han, Zhijie
author_facet He, Yijie
Huang, Lin
Tang, Yaqin
Yang, Zeyuan
Han, Zhijie
author_sort He, Yijie
collection PubMed
description 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 cis-splicing quantitative trait loci (sQTLs) analysis to identify the cis-acting loci and the affected differential AS events in MS and further explored the characteristics of these cis-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 cis-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.
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spelling pubmed-86331042021-12-02 Genome-wide Identification and Analysis of Splicing QTLs in Multiple Sclerosis by RNA-Seq Data He, Yijie Huang, Lin Tang, Yaqin Yang, Zeyuan Han, Zhijie Front Genet Genetics 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 cis-splicing quantitative trait loci (sQTLs) analysis to identify the cis-acting loci and the affected differential AS events in MS and further explored the characteristics of these cis-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 cis-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. Frontiers Media S.A. 2021-11-12 /pmc/articles/PMC8633104/ /pubmed/34868258 http://dx.doi.org/10.3389/fgene.2021.769804 Text en Copyright © 2021 He, Huang, Tang, Yang and Han. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Genetics
He, Yijie
Huang, Lin
Tang, Yaqin
Yang, Zeyuan
Han, Zhijie
Genome-wide Identification and Analysis of Splicing QTLs in Multiple Sclerosis by RNA-Seq Data
title Genome-wide Identification and Analysis of Splicing QTLs in Multiple Sclerosis by RNA-Seq Data
title_full Genome-wide Identification and Analysis of Splicing QTLs in Multiple Sclerosis by RNA-Seq Data
title_fullStr Genome-wide Identification and Analysis of Splicing QTLs in Multiple Sclerosis by RNA-Seq Data
title_full_unstemmed Genome-wide Identification and Analysis of Splicing QTLs in Multiple Sclerosis by RNA-Seq Data
title_short Genome-wide Identification and Analysis of Splicing QTLs in Multiple Sclerosis by RNA-Seq Data
title_sort genome-wide identification and analysis of splicing qtls in multiple sclerosis by rna-seq data
topic Genetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8633104/
https://www.ncbi.nlm.nih.gov/pubmed/34868258
http://dx.doi.org/10.3389/fgene.2021.769804
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