Systematic evaluation of isoform function in literature reports of alternative splicing

@article{Bhuiyan2018SystematicEO,
  title={Systematic evaluation of isoform function in literature reports of alternative splicing},
  author={Shamsuddin A. Bhuiyan and Sophia Ly and Minh Phan and Brandon Huntington and Ellie Hogan and Chao Chun Liu and James Liu and Paul Pavlidis},
  journal={BMC Genomics},
  year={2018},
  volume={19},
  url={https://api.semanticscholar.org/CorpusID:52113302}
}
It is concluded that the claim that alternative splicing vastly increases the functional repertoire of the genome is an extrapolation from a limited number of empirically supported cases, and that more work is needed to integrate experimental evidence and genome annotation databases.
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41 Citations
Background Citations
11
Methods Citations
2
Results Citations
1

41 Citations

Assessing the functional relevance of splice isoforms

A method, TRIFID, is developed to classify the functional importance of splice isoforms and it is believed that this method will generate valuable insights into the cellular importance of alternative splicing.

Alternative splicing is coupled to gene expression in a subset of variably expressed genes

A significant association of gene expression and splicing for 6874 of 141,043 exons in 1106 of 8314 genes with substantially variable expression in ten GTEx tissues is shown, suggesting that the coupling of expression and alternative splicing described here may provide an important gene regulatory mechanism that might be used in a variety of biological contexts.

Re-appraising the evidence for the source, regulation and function of p53-family isoforms

A critical appraisal of the current evidence for the origins, expression, functions and regulation of p53-family isoforms concludes that several putative isoforms remain poorly established and suggests that p53-family variants evolved partly through convergent rather than divergent evolution from the ancestral gene.

Alternative splicing is coupled to gene expression in a subset of variably expressed genes

Data from the Genotype-Tissue Expression project is leveraged to show a significant association of gene expression and splicing for 6874 of 141,043 exons in 1106 of 8314 genes with substantially variable expression in nine GTEx tissues suggesting an important regulatory mechanism.

An analysis of tissue-specific alternative splicing at the protein level

Tissue-specific alternative protein forms in the proteomics analysis were particularly abundant in nervous and muscle tissues and their genes had roles related to the cytoskeleton and either the structure of muscle fibres or cell-cell connections.

Random genetic drift sets an upper limit on mRNA splicing accuracy in metazoans

The results show a negative correlation between Ne proxies and the genome-wide AS rates among species, consistent with the drift barrier hypothesis, and it is shown that low abundance isoforms are depleted in functional AS events, and most likely correspond to errors.

Alternative splicing during mammalian organ development

Analysis of RNA-seq datasets from seven organs across seven species generates an alternative splicing (AS) atlas and shows that AS events provide functional gene diversification through generation of tissue- and time-specific transcript isoforms.

Functional and structural features of proteins associated with alternative splicing.

Alternative Transcripts Diversify Genome Function for Phenome Relevance to Health and Diseases

Manipulation using alternative exon splicing, alternative transcription start (ATS), and alternative polyadenylation (APA) sites are key to transcript diversity underlying health and disease, with ATS and APA site use having the highest impact on protein identity.

Transcripts’ evolutionary history and structural dynamics give mechanistic insights into the functional diversity of the JNK family

This work reconstructs phylogenetic forests relating 60 transcripts from the c-Jun N-terminal kinase (JNK) family observed in 7 species and identifies two alternative splicing events of ancient origin that induce subtle changes on the protein’s structural dynamics.

813 References

The Origins, Evolution, and Functional Potential of Alternative Splicing in Vertebrates

The data supports a model whereby the acquisition of functional AS has occurred throughout vertebrate evolution and is considered alongside amino acid change as a key mechanism in gene evolution, and indicates that functional NMD-linked AS is more widespread and ancient than previously thought.

The importance of identifying alternative splicing in vertebrate genome annotation

This work describes the incorporation of new sequencing and proteomics technologies into the annotation pipelines, which are used to identify and validate AS, and produces a rich geneset containing an average of 6.3 AS transcripts for every human multi-exon protein-coding gene.

Noisy Splicing Drives mRNA Isoform Diversity in Human Cells

A large class of low abundance isoforms is demonstrated, encompassing approximately 150,000 previously unannotated splice junctions in the authors' data, and sequence motifs involved in the recognition of exons are enriched in the vicinity of unconserved splice sites.

The fitness cost of mis-splicing is the main determinant of alternative splicing patterns

It is shown that in both normal and in NMD-deficient cells, AS rates strongly decrease with increasing expression level and with increasing number of introns, which indicates that genes under weaker selective pressure accumulate more maladaptive substitutions and are more prone to splicing errors.

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Evidence is now accumulating that alternative splicing coordinates physiologically meaningful changes in protein isoform expression and is a key mechanism to generate the complex proteome of multicellular organisms.

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Stochastic noise in splicing machinery

The hypothesis that most alternative splicing is a consequence of stochastic noise in the splicing machinery, and has no functional significance is supported.

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A rigorous analysis of the peptide evidence from eight large-scale proteomics experiments to assess the scale of alternative splicing that is detectable by high-resolution mass spectroscopy finds that most genes have a single dominant isoform at the protein level.

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The theory that isoform regulation is an important target of evolution in primates is supported by the analysis of transcriptomes of five tissues for six primate species, focusing on exons that are 1:1 orthologous in all six species.
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