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Nucleic Acids Research, 2001, Vol. 29, No. 11 2338-2348
© 2001 Oxford University Press

Computational analysis of candidate intron regulatory elements for tissue-specific alternative pre-mRNA splicing

Michael Brudno1,3, Mikhail S. Gelfand4, Sylvia Spengler1, Manfred Zorn1, Inna Dubchak1,* and John G. Conboy2

1National Energy Research Scientific Computing Center and 2Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA, 3Department of Computer Science, Stanford University, Stanford, CA 94305, USA and 4State Scientific Center for Biotechnology NII Genetika, Moscow 113545, Russia

Alternative pre-mRNA splicing is a major cellular process by which functionally diverse proteins can be generated from the primary transcript of a single gene, often in tissue-specific patterns. The current study investigates the hypothesis that splicing of tissue-specific alternative exons is regulated in part by control sequences in adjacent introns and that such elements may be recognized via computational analysis of exons sharing a highly specific expression pattern. We have identified 25 brain-specific alternative cassette exons, compiled a dataset of genomic sequences encompassing these exons and their adjacent introns and used word contrast algorithms to analyze key features of these nucleotide sequences. By comparison to a control group of constitutive exons, brain-specific exons were often found to possess the following: divergent 5' splice sites; highly pyrimidine-rich upstream introns; a paucity of GGG motifs in the downstream intron; a highly statistically significant over-representation of the hexanucleotide UGCAUG in the proximal downstream intron. UGCAUG was also found at a high frequency downstream of a smaller group of muscle-specific exons. Intriguingly, UGCAUG has been identified previously in a few intron splicing enhancers. Our results indicate that this element plays a much wider role than previously appreciated in the regulated tissue-specific splicing of many alternative exons.

* To whom correspondence should be addressed at: NERSC, Building 84-171, 1 Cyclotron Road, Berkeley, CA 94720, USA. Tel: +1 510 486 2419; Fax: +1 510 486 5717; Email: ildubchak{at}lbl.gov


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