Alternative isoform regulation in human tissue transcriptomes

Eric T. Wang, Rickard Sandberg, Shujun Luo, Irina Khrebtukova, Lu Zhang, Christine Mayr, Stephen F. Kingsmore, Gary P. Schroth and Christopher B. Burge ()
Additional contact information
Eric T. Wang: Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
Rickard Sandberg: Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
Shujun Luo: Illumina Inc., 25861 Industrial Boulevard, Hayward, California 94545, USA
Irina Khrebtukova: Illumina Inc., 25861 Industrial Boulevard, Hayward, California 94545, USA
Lu Zhang: Illumina Inc., 25861 Industrial Boulevard, Hayward, California 94545, USA
Christine Mayr: Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA
Stephen F. Kingsmore: National Center for Genome Resources, 2935 Rodeo Park Drive East, Santa Fe, New Mexico 87505, USA
Gary P. Schroth: Illumina Inc., 25861 Industrial Boulevard, Hayward, California 94545, USA
Christopher B. Burge: Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA

Nature, 2008, vol. 456, issue 7221, 470-476

Abstract: 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.

Date: 2008
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DOI: 10.1038/nature07509

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