Computational analysis of candidate intron regulatory elements for tissue-specific alternative pre-mRNA splicing.
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.
Brudno
M
M
National Energy Research Scientific Computing Center and Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
Gelfand
M S
MS
Spengler
S
S
Zorn
M
M
Dubchak
I
I
Conboy
J G
JG
D000465:Algorithms; D017398:Alternative Splicing; D001483:Base Sequence; D001921:Brain / Q000378:metabolism*; D004247:DNA / Q000235:genetics; D005091:Exons / Q000235:genetics; D005796:Genes / Q000235:genetics; D006801:Humans; D007438:Introns / Q000235:genetics*; D012322:RNA Precursors / Q000235:genetics*; D012045:Regulatory Sequences, Nucleic Acid
D012322:RNA Precursors; D004247:DNA