title: Alternative isoform regulation in human tissue transcriptomes.
abstract: Through alternative processing of pre-messenger RNAs, individual mammalian genes often produce multiple mRNA and protein isoforms that may have related, distinct or even opposing functions. Here we report an in-depth analysis of 15 diverse human tissue and cell line transcriptomes on the basis of deep sequencing of complementary DNA fragments, yielding a digital inventory of gene and mRNA isoform expression. Analyses in which sequence reads are mapped to exon-exon junctions indicated that 92-94% of human genes undergo alternative splicing, 86% with a minor isoform frequency of 15% or more. Differences in isoform-specific read densities indicated that most alternative splicing and alternative cleavage and polyadenylation events vary between tissues, whereas variation between individuals was approximately twofold to threefold less common. Extreme or 'switch-like' regulation of splicing between tissues was associated with increased sequence conservation in regulatory regions and with generation of full-length open reading frames. Patterns of alternative splicing and alternative cleavage and polyadenylation were strongly correlated across tissues, suggesting coordinated regulation of these processes, and sequence conservation of a subset of known regulatory motifs in both alternative introns and 3' untranslated regions suggested common involvement of specific factors in tissue-level regulation of both splicing and polyadenylation.
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Eric T
authors.initials: ET
authors.lastname: Wang
authors.forename: Rickard
authors.initials: R
authors.lastname: Sandberg
authors.forename: Shujun
authors.initials: S
authors.lastname: Luo
authors.forename: Irina
authors.initials: I
authors.lastname: Khrebtukova
authors.forename: Lu
authors.initials: L
authors.lastname: Zhang
authors.forename: Christine
authors.initials: C
authors.lastname: Mayr
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Kingsmore
authors.forename: Gary P
authors.initials: GP
authors.lastname: Schroth
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Burge
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D001483:Base Sequence; D002460:Cell Line; D005091:Exons / Q000235:genetics; D020869:Gene Expression Profiling; D006801:Humans; D016366:Open Reading Frames / Q000235:genetics; D009928:Organ Specificity; D026723:Polyadenylation; D020033:Protein Isoforms / Q000235:genetics*; D000072260:RNA Splicing Factors; D012333:RNA, Messenger / Q000032:analysis* / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism
chemical_list: D020033:Protein Isoforms; C455479:RBFOX1 protein, human; C454924:RBFOX2 protein, human; D000072260:RNA Splicing Factors; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D012097:Repressor Proteins