Identification and Analysis of Alternative Splicing Events Conserved in Human and Mouse

Alternative pre-mRNA splicing affects a majority of human genes and plays important roles in development and disease. Alternative splicing (AS) events conserved since the divergence of human and mouse are likely of primary biological importance, but relatively few of such events are known. Here we d...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 102; no. 8; pp. 2850 - 2855
Main Authors Yeo, Gene W., Van Nostrand, Eric, Holste, Dirk, Poggio, Tomaso, Burge, Christopher B., Sharp, Phillip A.
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 22.02.2005
National Acad Sciences
Subjects
Algorithms
Alternative Splicing
Animals
Base Sequence
Biological Evolution
Biological Sciences
Complementary DNA
Conserved Sequence
Evolution
Exons
Expressed Sequence Tags
Genes
Genetics
Humans
Introns
Mice
Oligonucleotides
Reverse transcriptase polymerase chain reaction
Ribonucleic acid
RNA
Splicing
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Summary:Alternative pre-mRNA splicing affects a majority of human genes and plays important roles in development and disease. Alternative splicing (AS) events conserved since the divergence of human and mouse are likely of primary biological importance, but relatively few of such events are known. Here we describe sequence features that distinguish exons subject to evolutionarily conserved AS, which we call alternative conserved exons (ACEs), from other orthologous human/mouse exons and integrate these features into an exon classification algorithm, ACESCAN. Genome-wide analysis of annotated orthologous human-mouse exon pairs identified ≈2,000 predicted ACEs. Alternative splicing was verified in both human and mouse tissues by using an RT-PCR-sequencing protocol for 21 of 30 (70%) predicted ACEs tested, supporting the validity of a majority of ACESCAN predictions. By contrast, AS was observed in mouse tissues for only 2 of 15 (13%) tested exons that had EST or cDNA evidence of AS in human but were not predicted ACEs, and AS was never observed for 11 negative control exons in human or mouse tissues. Predicted ACEs were much more likely to preserve the reading frame and less likely to disrupt protein domains than other AS events and were enriched in genes expressed in the brain and in genes involved in transcriptional regulation, RNA processing, and development. Our results also imply that the vast majority of AS events represented in the human EST database are not conserved in mouse.
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To whom correspondence may be sent at the present address: Crick–Jacobs Center for Computational and Theoretical Biology, The Salk Institute, La Jolla, CA 92037. E-mail: geneyeo@salk.edu. ¶To whom correspondence may be addressed. E-mail: cburge@mit.edu.
Communicated by Phillip A. Sharp, Massachusetts Institute of Technology, Cambridge, MA, December 30, 2004
Abbreviations: AS, alternative splicing; ACE, alternative conserved exon; ESE, exonic splicing enhancer; ESS, exonic splicing silencer; GO, Gene Ontology.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0409742102