Genome-wide detection of tissue-specific alternative splicing in the human transcriptome.
We have developed an automated method for discovering tissue-specific regulation of alternative splicing through a genome-wide analysis of expressed sequence tags (ESTs). Using this approach, we have identified 667 tissue-specific alternative splice forms of human genes. We validated our muscle-specific and brain-specific splice forms for known genes. A high fraction (8/10) were reported to have a matching tissue specificity by independent studies in the published literature. The number of tissue-specific alternative splice forms is highest in brain, while eye-retina, muscle, skin, testis and lymph have the greatest enrichment of tissue-specific splicing. Overall, 10-30% of human alternatively spliced genes in our data show evidence of tissue-specific splice forms. Seventy-eight percent of our tissue-specific alternative splices appear to be novel discoveries. We present bioinformatics analysis of several tissue-specific splice forms, including automated protein isoform sequence and domain prediction, showing how our data can provide valuable insights into gene function in different tissues. For example, we have discovered a novel kidney-specific alternative splice form of the WNK1 gene, which appears to specifically disrupt its N-terminal kinase domain and may play a role in PHAII hypertension. Our database greatly expands knowledge of tissue-specific alternative splicing and provides a comprehensive dataset for investigating its functional roles and regulation in different human tissues.
Xu
Qiang
Q
Molecular Biology Institute and Department of Chemistry and Biochemistry, University of California-Los Angeles, Los Angeles, CA 90095-1570, USA.
Modrek
Barmak
B
Lee
Christopher
C
D017398:Alternative Splicing / Q000235:genetics*; D000595:Amino Acid Sequence; D001921:Brain / Q000378:metabolism; D019295:Computational Biology / Q000706:statistics & numerical data; D004268:DNA-Binding Proteins / Q000235:genetics; D020224:Expressed Sequence Tags; D005260:Female; D020869:Gene Expression Profiling; D015723:Gene Library; D015894:Genome, Human; D006801:Humans; D050838:Interferon Regulatory Factor-3; D008297:Male; D008969:Molecular Sequence Data; D020033:Protein Isoforms / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic / Q000235:genetics*; D020764:cdc42 GTP-Binding Protein / Q000235:genetics
D004268:DNA-Binding Proteins; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D020033:Protein Isoforms; D014157:Transcription Factors; D020764:cdc42 GTP-Binding Protein