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Genetic variation of pre-mRNA alternative splicing in human populations.

ABSTRACT: The precise splicing outcome of a transcribed gene is controlled by complex interactions between cis regulatory splicing signals and trans-acting regulators. In higher eukaryotes, alternative splicing is a prevalent mechanism for generating transcriptome and proteome diversity. Alternative splicing can modulate gene function, affect organismal phenotype and cause disease. Common genetic variation that affects splicing regulation can lead to differences in alternative splicing between human individuals and consequently impact expression level or protein function. In several well-documented examples, such natural variation of alternative splicing has indeed been shown to influence disease susceptibility and drug response. With new microarray and sequencing-based genomic technologies that can analyze eukaryotic transcriptomes at the exon or nucleotide level, it has become possible to globally compare the alternative splicing profiles across human individuals in any tissue or cell type of interest. Recent large-scale transcriptome studies using high-density splicing-sensitive microarray and deep RNA sequencing (RNA-Seq) have revealed widespread genetic variation of alternative splicing in humans. In the future, an extensive catalog of alternative splicing variation in human populations will help elucidate the molecular underpinnings of complex traits and human diseases, and shed light on the mechanisms of splicing regulation in human cells.

SUBMITTER: Lu ZX

PROVIDER: S-EPMC3339278 | biostudies-literature | 2012 Jul-Aug

REPOSITORIES: biostudies-literature

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Genetic variation of pre-mRNA alternative splicing in human populations.

Lu Zhi-Xiang ZX Jiang Peng P Xing Yi Y

Wiley interdisciplinary reviews. RNA 20111117 4

The precise splicing outcome of a transcribed gene is controlled by complex interactions between cis regulatory splicing signals and trans-acting regulators. In higher eukaryotes, alternative splicing is a prevalent mechanism for generating transcriptome and proteome diversity. Alternative splicing can modulate gene function, affect organismal phenotype and cause disease. Common genetic variation that affects splicing regulation can lead to differences in alternative splicing between human indiv ...[more]

PMID: 22095823

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Project description:BackgroundMultiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system to which a genetic predisposition contributes. Over 200 genetic regions have been associated with increased disease risk, but the disease-causing variants and their functional impact at the molecular level are mostly poorly defined. We hypothesized that single-nucleotide polymorphisms (SNPs) have an impact on pre-mRNA splicing in MS.MethodsOur study focused on 10 bioinformatically prioritized SNP-gene pairs, in which the SNP has a high potential to alter alternative splicing events (ASEs). We tested for differential gene expression and differential alternative splicing in B cells from MS patients and healthy controls. We further examined the impact of the SNP genotypes on ASEs and on splice isoform expression levels. Novel genotype-dependent effects on splicing were verified with splicing reporter minigene assays.ResultsWe were able to confirm previously described findings regarding the relation of MS-associated SNPs with the ASEs of the pre-mRNAs from GSDMB and SP140. We also observed an increased IL7R exon 6 skipping when comparing relapsing and progressive MS patients to healthy subjects. Moreover, we found evidence that the MS risk alleles of the SNPs rs3851808 (EFCAB13), rs1131123 (HLA-C), rs10783847 (TSFM), and rs2014886 (TSFM) may contribute to a differential splicing pattern. Of particular interest is the genotype-dependent exon skipping of TSFM due to the SNP rs2014886. The minor allele T creates a donor splice site, resulting in the expression of the exon 3 and 4 of a short TSFM transcript isoform, whereas in the presence of the MS risk allele C, this donor site is absent, and thus the short transcript isoform is not expressed.ConclusionIn summary, we found that genetic variants from MS risk loci affect pre-mRNA splicing. Our findings substantiate the role of ASEs with respect to the genetics of MS. Further studies on how disease-causing genetic variants may modify the interactions between splicing regulatory sequence elements and RNA-binding proteins can help to deepen our understanding of the genetic susceptibility to MS.

Dataset Information

Genetic variation of pre-mRNA alternative splicing in human populations.

Publications

Genetic variation of pre-mRNA alternative splicing in human populations.

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