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.
2020-06-29 | GSE151942 | GEO
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.
| S-EPMC7673789 | biostudies-literature
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.
2015-05-20 | PXD001449 | Pride
Project description:Glycine max Alternatively Spliced Transcript Detecting Microarray (GmASDM).
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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:The Exon Junction Complex (EJC) has roles in mRNA export and cytoplasmic quality control. Yet EJC is recruited to pre-mRNA by the spliceosome, prior to the second catalytic step of splicing. Because splicing often occurs co-transcriptionally, EJC can be deposited on nascent RNA almost immediately after introns are synthesized and excised, raising the question of whether EJC regulates downstream RNA processing decisions. Here, we show that degron-mediated depletion of EJC component EIF4A3 leads to substantial skipping of neighboring pairs of two or more exons. These exon skipping events occurred on the same molecule of mRNA, detected by long read sequencing, suggesting that “exon blocks” require EJC for inclusion. Introns flanking EJC-dependent exon blocks were longer and spliced after internal introns. Thus, block exons form a larger EJC-marked exon prior to surrounding splicing events. These findings identify a previously unknown nuclear function of EJC that coordinates co-transcriptional inclusion of exon blocks.
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Project description:An alternatively spliced p62 isoform promotes breast cancer chemoresistance
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Project description:We identified an alternatively spliced UMOD which is uniquely localized intracellularly. This intracellular isoform enhanced mitochondrial function. To understand its molecular mechanism, we performed affinity-purification coupled to mass spectrometry using MDCK cell lysate expressing UMOD variant. We prepared MDCK cells which express mock (negative control), wild-type human UMOD or alternatively spliced human UMOD. UMOD was isolated by Immunoprecipitation and interacting proteins were identified by mass spectrometry proteomics analysis.
2024-03-15 | MSV000094329 | MassIVE
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.
2011-03-07 | E-GEOD-23016 | biostudies-arrayexpress
Project description:Alu repetitive elements are found in approximately 1.4 million copies in the human genome, comprising more than one-tenth of it. Numerous studies describe exonizations of Alu elements, that is, splicing-mediated insertions of parts of Alu sequences into mature mRNAs. To study the connection between the exonization of Alu elements and alternative splicing, we used a database of ESTs and cDNAs aligned to the human genome. We compiled two exon sets, one of 1176 alternatively spliced internal exons, and another of 4151 constitutively spliced internal exons. Sixty one alternatively spliced internal exons (5.2%) had a significant BLAST hit to an Alu sequence, but none of the constitutively spliced internal exons had such a hit. The vast majority (84%) of the Alu-containing exons that appeared within the coding region of mRNAs caused a frame-shift or a premature termination codon. Alu-containing exons were included in transcripts at lower frequencies than alternatively spliced exons that do not contain an Alu sequence. These results indicate that internal exons that contain an Alu sequence are predominantly, if not exclusively, alternatively spliced. Presumably, evolutionary events that cause a constitutive insertion of an Alu sequence into an mRNA are deleterious and selected against.
| S-EPMC186627 | biostudies-literature