title: Unusual intron conservation near tissue-regulated exons found by splicing microarrays.
abstract: Alternative splicing contributes to both gene regulation and protein diversity. To discover broad relationships between regulation of alternative splicing and sequence conservation, we applied a systems approach, using oligonucleotide microarrays designed to capture splicing information across the mouse genome. In a set of 22 adult tissues, we observe differential expression of RNA containing at least two alternative splice junctions for about 40% of the 6,216 alternative events we could detect. Statistical comparisons identify 171 cassette exons whose inclusion or skipping is different in brain relative to other tissues and another 28 exons whose splicing is different in muscle. A subset of these exons is associated with unusual blocks of intron sequence whose conservation in vertebrates rivals that of protein-coding exons. By focusing on sets of exons with similar regulatory patterns, we have identified new sequence motifs implicated in brain and muscle splicing regulation. Of note is a motif that is strikingly similar to the branchpoint consensus but is located downstream of the 5' splice site of exons included in muscle. Analysis of three paralogous membrane-associated guanylate kinase genes reveals that each contains a paralogous tissue-regulated exon with a similar tissue inclusion pattern. While the intron sequences flanking these exons remain highly conserved among mammalian orthologs, the paralogous flanking intron sequences have diverged considerably, suggesting unusually complex evolution of the regulation of alternative splicing in multigene families.
authors.affiliation: Department of Computer Science, Baskin School of Engineering, University of California Santa Cruz, Santa Cruz, California, USA.
authors.forename: Charles W
authors.initials: CW
authors.lastname: Sugnet
authors.forename: Karpagam
authors.initials: K
authors.lastname: Srinivasan
authors.forename: Tyson A
authors.initials: TA
authors.lastname: Clark
authors.forename: Georgeann
authors.initials: G
authors.lastname: O'Brien
authors.forename: Melissa S
authors.initials: MS
authors.lastname: Cline
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.forename: Alan
authors.initials: A
authors.lastname: Williams
authors.forename: David
authors.initials: D
authors.lastname: Kulp
authors.forename: John E
authors.initials: JE
authors.lastname: Blume
authors.forename: David
authors.initials: D
authors.lastname: Haussler
authors.forename: Manuel
authors.initials: M
authors.lastname: Ares
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000145:classification / Q000235:genetics; D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000378:metabolism; D017124:Conserved Sequence; D019143:Evolution, Molecular; D005091:Exons / Q000235:genetics*; D006801:Humans; D007438:Introns / Q000235:genetics*; D008565:Membrane Proteins / Q000145:classification / Q000235:genetics; D051379:Mice; D008969:Molecular Sequence Data; D009132:Muscles / Q000378:metabolism; D009479:Neuropeptides / Q000145:classification / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D009928:Organ Specificity; D020033:Protein Isoforms / Q000235:genetics; D016415:Sequence Alignment
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D008565:Membrane Proteins; D009479:Neuropeptides; D020033:Protein Isoforms