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Systems analysis of alternative splicing and its regulation

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Abstract Alternative splicing (AS) has emerged as a key mechanism that accounts for gene expression diversity in metazoan organisms. Splicing is tightly regulated by a repertoire of RNA and protein factors and RNA sequence elements that function in a cooperative manner. Systems‐level experimental and computational approaches have been instrumental in establishing comprehensive profiles of transcript variants generated by AS. In addition, systems biology approaches are starting to define how combinatorial splicing regulation shapes the complex splicing phenotypes observed in different tissue types and developmental stages and under different conditions. Here, we review recent progress in these areas. Copyright © 2010 John Wiley & Sons, Inc. This article is categorized under: Biological Mechanisms > Regulatory Biology

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Methods for the analysis of alternative splicing. (a) Expressed sequence tag and cDNA alignments for a hypothetical gene in which one exon (red) is alternatively spliced. (b) Schematics of probe design of different types of microarrays. Probes spanning different exon junctions are illustrated with intervening dashed lines. (c) Short reads from RNA‐Seq are mapped to the hypothetical gene. Reads mapped to both annotated [as in (a)] exons and exon–exon junctions are illustrated. In addition, some reads may map to annotated intronic regions indicating the possible existence of a novel exon.

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Schematics of splicing regulatory mechanisms. Exons are represented by blue boxes, introns by straight or curved lines. Functional interactions among splicing regulatory proteins and snRNPs are delineated by arcs. Flat‐headed arcs denote antagonistic relationships. Arcs with arrowheads denote synergistic/enhancing interactions. For some interactions, intermediate proteins may be involved which are not shown. Various regulatory patterns are assembled together compactly for illustration purposes only.

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Splice site definition via core splicing signals and auxiliary splicing cis‐elements in the BZAP45 gene. (a) The genomic sequence of BZAP45 was scored via the MaxEnt program74 for their match to consensus 5′ss (left‐facing bracket) and 3′ss (right‐facing bracket). The height of a bracket is proportional to the splice site score. Authentic exons of the gene are represented by blue boxes. (b) Prediction of exons via the ExonScan algorithm73 using the splice site scores only, splice site scores and scores of RESCUE‐ESEs,75 or splice site scores and scores of both RESCUE‐ESEs75 and FAS‐ESS.73.

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