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A compatible exon-exon junction database for the identification of exon skipping events using tandem mass spectrum data.

ABSTRACT: Alternative splicing is an important gene regulation mechanism. It is estimated that about 74% of multi-exon human genes have alternative splicing. High throughput tandem (MS/MS) mass spectrometry provides valuable information for rapidly identifying potentially novel alternatively-spliced protein products from experimental datasets. However, the ability to identify alternative splicing events through tandem mass spectrometry depends on the database against which the spectra are searched.We wrote scripts in perl, Bioperl, mysql and Ensembl API and built a theoretical exon-exon junction protein database to account for all possible combinations of exons for a gene while keeping the frame of translation (i.e., keeping only in-phase exon-exon combinations) from the Ensembl Core Database. Using our liver cancer MS/MS dataset, we identified a total of 488 non-redundant peptides that represent putative exon skipping events.Our exon-exon junction database provides the scientific community with an efficient means to identify novel alternatively spliced (exon skipping) protein isoforms using mass spectrometry data. This database will be useful in annotating genome structures using rapidly accumulating proteomics data.

SUBMITTER: Mo F

PROVIDER: S-EPMC2636810 | biostudies-other | 2008 Dec

REPOSITORIES: biostudies-other

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A compatible exon-exon junction database for the identification of exon skipping events using tandem mass spectrum data.

Mo Fan F Hong Xu X Gao Feng F Du Lin L Wang Jun J Omenn Gilbert S GS Lin Biaoyang B

BMC bioinformatics 20081216

<h4>Background</h4>Alternative splicing is an important gene regulation mechanism. It is estimated that about 74% of multi-exon human genes have alternative splicing. High throughput tandem (MS/MS) mass spectrometry provides valuable information for rapidly identifying potentially novel alternatively-spliced protein products from experimental datasets. However, the ability to identify alternative splicing events through tandem mass spectrometry depends on the database against which the spectra a ...[more]

PMID: 19087293

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Project description:BackgroundAt least 90% of human genes are alternatively spliced. Alternative splicing has an important function regulating gene expression and miss-splicing can contribute to risk for human diseases, including Alzheimer's disease (AD).MethodsWe developed a splicing decision model as a molecular mechanism to identify functional exon skipping events and genetic variation affecting alternative splicing on a genome-wide scale by integrating genomics, transcriptomics, and neuroimaging data in a systems biology approach. In this study, we analyzed RNA-Seq data of hippocampus brain tissue from Alzheimer's disease (AD; n = 24) and cognitively normal elderly controls (CN; n = 50) and identified three exon skipping events in two genes (RELN and NOS1) as significantly associated with AD (corrected p-value < 0.05 and fold change > 1.5). Next, we identified single-nucleotide polymorphisms (SNPs) affecting exon skipping events using the splicing decision model and then performed an association analysis of SNPs potentially affecting three exon skipping events with a global cortical measure of amyloid-β deposition measured by [18F] Florbetapir position emission tomography (PET) scan as an AD-related quantitative phenotype. A whole-brain voxel-based analysis was also performed.ResultsTwo exons in RELN and one exon in NOS1 showed significantly lower expression levels in the AD participants compared to CN participants, suggesting that the exons tend to be skipped more in AD. We also showed the loss of the core protein structure due to the skipped exons using the protein 3D structure analysis. The targeted SNP-based association analysis identified one intronic SNP (rs362771) adjacent to the skipped exon 24 in RELN as significantly associated with cortical amyloid-β levels (corrected p-value < 0.05). This SNP is within the splicing regulatory element, i.e., intronic splicing enhancer. The minor allele of rs362771 conferred decreases in cortical amyloid-β levels in the right temporal and bilateral parietal lobes.ConclusionsOur results suggest that exon skipping events and splicing-affecting SNPs in the human hippocampus may contribute to AD pathogenesis. Integration of multiple omics and neuroimaging data provides insights into possible mechanisms underlying AD pathophysiology through exon skipping and may help identify novel therapeutic targets.

Project description:Exon skipping (ES), the most common alternative splicing event, has been reported to contribute to diverse human diseases due to the loss of functional domains/sites or frameshifting of the open reading frame (ORF) and noticed as therapeutic targets. Accumulating transcriptomic studies of aging brains show the splicing disruption is a widespread hallmark of neurodegenerative diseases such as Alzheimer's disease (AD). Here, we built ExonSkipAD, the ES annotation database aiming to provide a resource/reference for functional annotation of ES events in AD and identify therapeutic targets in exon units. We identified 16 414 genes that have ~156 K, ~ 69 K, ~ 231 K ES events from the three representative AD cohorts of ROSMAP, MSBB and Mayo, respectively. For these ES events, we performed multiple functional annotations relating to ES mechanisms or downstream. Specifically, through the functional feature retention studies followed by the open reading frames (ORFs), we identified 275 important cellular regulators that might lose their cellular regulator roles due to exon skipping in AD. ExonSkipAD provides twelve categories of annotations: gene summary, gene structures and expression levels, exon skipping events with PSIs, ORF annotation, exon skipping events in the canonical protein sequence, 3'-UTR located exon skipping events lost miRNA-binding sites, SNversus in the skipped exons with a depth of coverage, AD stage-associated exon skipping events, splicing quantitative trait loci (sQTLs) in the skipped exons, correlation with RNA-binding proteins, and related drugs & diseases. ExonSkipAD will be a unique resource of transcriptomic diversity research for understanding the mechanisms of neurodegenerative disease development and identifying potential therapeutic targets in AD. Significance AS the first comprehensive resource of the functional genomics of the alternative splicing events in AD, ExonSkipAD will be useful for many researchers in the fields of pathology, AD genomics and precision medicine, and pharmaceutical and therapeutic researches.

Dataset Information

A compatible exon-exon junction database for the identification of exon skipping events using tandem mass spectrum data.

Publications

A compatible exon-exon junction database for the identification of exon skipping events using tandem mass spectrum data.

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