Understanding alternative splicing: towards a cellular code

Matlin, Arianne J.; Clark, Francis; Smith, Christopher W.

doi:10.1038/nrm1645

Cited by 1,161 publications

(1,057 citation statements)

References 141 publications

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“…This is best demonstrated by genes in arthropods that contain both multiple MXE clusters (“multi‐cluster”) and large clusters with up to 53 MXEs such as in the Drosophila Dscam genes (Graveley et al , 2004; Pillmann et al , 2011). This is in strong contrast to mutually exclusive splicing in vertebrates as there is to date no evidence of multi‐cluster or higher order MXE clusters (Matlin et al , 2005; Pan et al , 2008; Wang et al , 2008; Gerstein et al , 2014; Abascal et al , 2015a,b). …”

Section: Resultsmentioning

confidence: 93%

“…Alternative splicing of pre‐messenger RNAs is a mechanism common to almost all eukaryotes to generate a plethora of protein variants out of a limited number of genes (Matlin et al , 2005; Nilsen & Graveley, 2010; Lee & Rio, 2015). High‐throughput studies suggested that not only 95–100% of all multi‐exon genes in human are affected (Pan et al , 2008; Wang et al , 2008; Gerstein et al , 2014) but also that alternative splicing patterns strongly diverged between vertebrate lineages implying a pronounced role in the evolution of phenotypic complexity (Barbosa‐Morais et al , 2012; Merkin et al , 2012).…”

Section: Introductionmentioning

confidence: 99%

“…Opposed to arthropods, current evidence suggests that vertebrate MXEs only occur in pairs (Matlin et al , 2005; Gerstein et al , 2014; Abascal et al , 2015a), and genomewide estimates in human range from 118 (Suyama, 2013) to at most 167 cases (Wang et al , 2008). Despite these relatively few reported cases, mutually exclusive splicing might be far more frequent in humans than currently anticipated, as has been recently revealed in the model organism Drosophila melanogaster (Hatje & Kollmar, 2013).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

The landscape of human mutually exclusive splicing

Hatje

Rahman

Vidal

et al. 2017

Molecular Systems Biology

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Mutually exclusive splicing of exons is a mechanism of functional gene and protein diversification with pivotal roles in organismal development and diseases such as Timothy syndrome, cardiomyopathy and cancer in humans. In order to obtain a first genomewide estimate of the extent and biological role of mutually exclusive splicing in humans, we predicted and subsequently validated mutually exclusive exons (MXEs) using 515 publically available RNA‐Seq datasets. Here, we provide evidence for the expression of over 855 MXEs, 42% of which represent novel exons, increasing the annotated human mutually exclusive exome more than fivefold. The data provide strong evidence for the existence of large and multi‐cluster MXEs in higher vertebrates and offer new insights into MXE evolution. More than 82% of the MXE clusters are conserved in mammals, and five clusters have homologous clusters in Drosophila. Finally, MXEs are significantly enriched in pathogenic mutations and their spatio‐temporal expression might predict human disease pathology.

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Section: Resultsmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The landscape of human mutually exclusive splicing

Hatje

Rahman

Vidal

et al. 2017

Molecular Systems Biology

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“…Tight regulation of the expression of splicing factors is necessary for proper splicing outcomes (Matlin, Clark, & Smith, 2005; Shin & Manley, 2004), and splicing factors themselves exhibit altered patterns of age‐related splicing (Rodríguez et al, 2016). In our data, we observe age‐associated differential splicing of several splicing‐related genes including muscleblind ( mbl ) and Protein on ecdysone puffs ( Pep) .…”

Section: Discussionmentioning

confidence: 99%

Proper splicing contributes to visual function in the aging Drosophila eye

et al. 2018

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Changes in splicing patterns are a characteristic of the aging transcriptome; however, it is unclear whether these age‐related changes in splicing facilitate the progressive functional decline that defines aging. In Drosophila, visual behavior declines with age and correlates with altered gene expression in photoreceptors, including downregulation of genes encoding splicing factors. Here, we characterized the significance of these age‐regulated splicing‐associated genes in both splicing and visual function. To do this, we identified differential splicing events in either the entire eye or photoreceptors of young and old flies. Intriguingly, aging photoreceptors show differential splicing of a large number of visual function genes. In addition, as shown previously for aging photoreceptors, aging eyes showed increased accumulation of circular RNAs, which result from noncanonical splicing events. To test whether proper splicing was necessary for visual behavior, we knocked down age‐regulated splicing factors in photoreceptors in young flies and examined phototaxis. Notably, many of the age‐regulated splicing factors tested were necessary for proper visual behavior. In addition, knockdown of individual splicing factors resulted in changes in both alternative splicing at age‐spliced genes and increased accumulation of circular RNAs. Together, these data suggest that cumulative decreases in splicing factor expression could contribute to the differential splicing, circular RNA accumulation, and defective visual behavior observed in aging photoreceptors.

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“…Whereas genes are comprised of a relatively unvarying linear sequence of nucleotides, the proteins resulting from such genes are much more varied in structure, function and dynamic range (at least in our current understanding of gene regulation). This increased complexity is a result of alternative gene splicing (Matlin et al, 2005), post-translational modification (Walsh, 2006) and 'Omic' disciplines and systems biology in cattle breeding protein/protein interactions (Royer, 1999). Many hundreds of post-translational modifications exist including proteolytic cleavage, acylation, glycosylation, methylation, phosphorylation, sulfation, and di-sulfide bond formation (Krishna and Wold, 1998).…”

Section: Proteomicsmentioning

confidence: 99%

The integration of ‘omic’ disciplines and systems biology in cattle breeding

Berry

Meade

Mullen

et al. 2011

Animal

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Enormous progress has been made in the selection of animals, including cattle, for specific traits using traditional quantitative genetics approaches. Nevertheless, considerable variation in phenotypes remains unexplained, and therefore represents potential additional gain for animal production. In addition, the paradigm shift in new disciplines now being applied to animal breeding represents a powerful opportunity to prise open the 'black box' underlying the response to selection and fully understand the genetic architecture controlling the traits of interest. A move away from traditional approaches of animal breeding toward systems approaches using integrative analysis of data from the 'omic' disciplines represents a multitude of exciting opportunities for animal breeding going forward as well as providing alternatives for overcoming some of the limitations of traditional approaches such as the expressed phenotype being an imperfect predictor of the individual's true genetic merit, or the phenotype being only expressed in one gender or late in the lifetime of an animal. This review aims to discuss these opportunities from the perspective of their potential application and contribution to cattle breeding. Harnessing the potential of this paradigm shift also poses some new challenges for animal scientists -and they will also be discussed.

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Understanding alternative splicing: towards a cellular code

Cited by 1,161 publications

References 141 publications

The landscape of human mutually exclusive splicing

The landscape of human mutually exclusive splicing

Proper splicing contributes to visual function in the aging Drosophila eye

The integration of ‘omic’ disciplines and systems biology in cattle breeding

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