Mutations primarily alter the inclusion of alternatively spliced exons
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA637776 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11940700_1.fastq.gz | Fastqsanger.gz | |||
| SRR11940700_2.fastq.gz | Fastqsanger.gz | |||
| SRR11940701_1.fastq.gz | Fastqsanger.gz | |||
| SRR11940701_2.fastq.gz | Fastqsanger.gz | |||
| SRR11940702_1.fastq.gz | Fastqsanger.gz |
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Project description:Systematic mutagenesis has revealed that synonymous, non-synonymous and intronic mutations frequently alter the inclusion levels of alternatively spliced exons, suggesting that altered splicing might be a common mechanism by which mutations cause disease. However, most exons expressed in any cell are highly-included in mature mRNAs. Here, by performing deep mutagenesis of highly-included exons and by analysing the association between sequence variation and exon inclusion across the genome, we report that mutations only very rarely alter the inclusion of highly-included exons. This is true for both exonic and intronic mutations as well as for perturbations in trans. Therefore, mutations that affect splicing are not evenly distributed across the genome but are focussed in and around alternatively spliced exons with intermediate inclusion levels. These results provide a resource for prioritising synonymous and other variants as disease-causing mutations.
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Project description:Genetic analyses and systematic mutagenesis have revealed that synonymous, non-synonymous and intronic mutations frequently alter the inclusion levels of alternatively spliced exons, consistent with the concept that altered splicing might be a common mechanism by which mutations cause disease. However, most exons expressed in any cell are highly-included in mature mRNAs. Here, by performing deep mutagenesis of highly-included exons and by analysing the association between genome sequence variation and exon inclusion across the transcriptome, we report that mutations only very rarely alter the inclusion of highly-included exons. This is true for both exonic and intronic mutations as well as for perturbations in trans. Therefore, mutations that affect splicing are not evenly distributed across primary transcripts but are focussed in and around alternatively spliced exons with intermediate inclusion levels. These results provide a resource for prioritising synonymous and other variants as disease-causing mutations.
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Project description:Alternative splicing of mRNA diversifies the function of human proteins, with tissue- and cell-specific protein isoforms being the most difficult to validate. While transcriptomic experiments enable the detection of many alternatively spliced transcripts, it is not known if these transcripts have protein-coding potential. We recently published the PG Nexus pipeline, which facilitates high confidence validation of exons and exon-exon junctions of spliced transcripts by integrating transcriptomics and proteomics data. Using the PG Nexus, we analyzed undifferentiated human mesenchymal stem cells and compared the number of protein isoforms validated using different protein sequence database, including public online databases and RNA-seq derived databases. With significant overlaps with other databases, we identified 8,011 exons and 3,824 splice junctions with the Ensembl database. Both exonic and junction peptides were important for protein isoform validation. The Ensembl database consistently outperformed the other data sources, but predicted open reading frames from RNA-seq derived transcripts were comparable, with only 6 less splice junctions validated. Using proteotypic and isoform-specific peptides, we validated 462 protein isoforms. This number increases to 1,083 if multiple proteotypic peptides per protein are included. Multiplexing proteotypic peptides in SRM assays or similar experiments will increase the confidence and coverage of protein isoform validation experiments.
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Project description:IL-4d2 is a natural splice variant of IL-4 which lacks the region encoded by the second exon. Numerous recent reports suggested that the expression levels of IL-4d2 change in various diseases, especially those with pulmonary involvement, but the effects of IL-4d2 on the lungs in vivo have never been studied. Replication-deficient adenovirus-mediated gene delivery of mouse IL-4d2 to mouse lungs in vivo was used, and the effects compared with similar adenoviral delivery of mouse IL-4 or with infection with a NULL viral construct. The objective was to determine whether full-length wild-type Interleukin-4 encoded by exons 1-4 (IL-4) and alternatively spliced variant econded by exons 1,3, and 4 (IL-4d2) differentially affect gene expression in the lungs in vivo. The results show that IL-4d2 and IL-4 affected global gene expression differentially. Keywords: Comparative analysis of gene delivery of alternative splice variants in vivo
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Project description:IL-4d2 is a natural splice variant of IL-4 which lacks the region encoded by the second exon. Numerous recent reports suggested that the expression levels of IL-4d2 change in various diseases, especially those with pulmonary involvement, but the effects of IL-4d2 on the lungs in vivo have never been studied. Replication-deficient adenovirus-mediated gene delivery of mouse IL-4d2 to mouse lungs in vivo was used, and the effects compared with similar adenoviral delivery of mouse IL-4 or with infection with a NULL viral construct. The objective was to determine whether full-length wild-type Interleukin-4 encoded by exons 1-4 (IL-4) and alternatively spliced variant econded by exons 1,3, and 4 (IL-4d2) differentially affect gene expression in the lungs in vivo. The results show that IL-4d2 and IL-4 affected global gene expression differentially. Keywords: Comparative analysis of gene delivery of alternative splice variants in vivo There were three mice overexpressing mouse IL-4 in their lungs, three mice overexpressing mouse IL-4d2 in their lungs, and three mice similarly infected with control AdV-NULL virus not encoding a cytokine.
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Project description:The goal of this study was to determine the role of RBM25 in pre-mRNA splicing and examine whether lysine 77 contributes to this function.
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Project description:The split structure of most mammalian protein-coding genes allows for the potential to produce multiple different mRNA and protein isoforms from a single gene locus through the process of alternative splicing (AS). We propose a computational approach called UNCOVER based on a pair hidden Markov model to discover conserved coding exonic sequences subject to AS that have so far gone undetected. Applying UNCOVER to orthologous introns of known human and mouse genes predicts skipped exons or retained introns present in both species, while discriminating them from conserved noncoding sequences. The accuracy of the model is evaluated on a curated set of genes with known conserved AS events. The prediction of skipped exons in the approximately 1% of the human genome represented by the ENCODE regions leads to more than 50 new exon candidates. Five novel predicted AS exons were validated by RT-PCR and sequencing analysis of 15 introns with strong UNCOVER predictions and lacking EST evidence. These results imply that a considerable number of conserved exonic sequences and associated isoforms are still completely missing from the current annotation of known genes. UNCOVER also identifies a small number of candidates for conserved intron retention.
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