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A Reporter Based Cellular Assay for Monitoring Splicing Efficiency
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Does conservation account for splicing patterns?

Michael Wainberg1, Babak Alipanahi1, Brendan Frey2,3,4

  • 1Department of Electrical and Computer Engineering, University of Toronto, 10 King's College Road, Toronto, M5S 3G4, Canada.

BMC Genomics
|October 9, 2016
PubMed
Summary
This summary is machine-generated.

Alternative mRNA splicing generates protein diversity. A new computational model reveals splice site conservation predicts splicing patterns, suggesting novel regulatory elements and proteins drive evolutionary changes in gene expression.

Keywords:
Alternative splicingConservationSplicing regulation

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Area of Science:

  • Genetics and Genomics
  • Molecular Biology
  • Bioinformatics

Background:

  • Alternative mRNA splicing, particularly exon skipping, is crucial for proteomic diversity and organismal differentiation.
  • Understanding the regulatory mechanisms of alternative splicing is key to deciphering gene expression complexity.

Purpose of the Study:

  • To develop a computational model for predicting alternative splicing with high accuracy.
  • To identify key sequence features that govern alternative splicing patterns.
  • To investigate the evolutionary role of splicing regulation.

Main Methods:

  • Development of a novel computational model for predicting percent-spliced-in values of cassette exons.
  • Utilized splice junction conservation scores (e.g., phastCons) as primary predictive features.
  • Defined and analyzed intronic splicing regulatory elements (ISREs) independent of known motifs.

Main Results:

  • The model accurately predicts alternative splicing without relying on handcrafted biological features.
  • Conservation of splice junctions and flanking introns is a powerful predictor of splicing outcomes.
  • Intronic splicing regulation is localized near splice sites, and conserved intronic elements act as regulators.
  • Increased flanking intron conservation correlates with decreased exon inclusion.
  • Identified novel intronic splicing regulatory elements (ISREs) not matching known binding sites.

Conclusions:

  • The emergence of cis-acting splicing inhibitors may explain the evolutionary shift from constitutive to alternative splicing.
  • The identified ISREs suggest the existence of novel RNA-binding proteins or uncharacterized roles for known proteins in splicing regulation.