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. 2002 Sep 1;30(17):3754-66.
doi: 10.1093/nar/gkf492.

Genome-wide detection of tissue-specific alternative splicing in the human transcriptome

Qiang Xu  1 , Barmak Modrek, Christopher Lee
Affiliations

Genome-wide detection of tissue-specific alternative splicing in the human transcriptome

Qiang Xu et al. Nucleic Acids Res. .

Abstract

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.

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Figures

Figure 1
Figure 1
Brain-specific alternative splicing of IRF3. (A) Genomic structure of the IRF3 gene. Exons are shown as boxes and colors show alternative exons. Splice a is specific to brain. (B) The two alternative forms of IRF3 mRNA inferred from the expressed sequence data. The protein coding region is indicated by an arrow beneath each form. (C) Schematic representation of the IRF3 protein. The DNA-binding domain, the NES element, the proline-rich region and the C-terminal IRF association domain are indicated. Dashed lines mark the boundaries of the DNA-binding domain.
Figure 2
Figure 2
Tissue distribution of human tissue-specific alternative splicing. Areas on the pie chart are proportional to the total number of alternative splices with high confidence tissue specificity for a particular tissue.
Figure 3
Figure 3
Enrichment of tissue-specific alternative splicing in 30 human tissues. The y-axis shows the enrichment factor for each tissue, defined as the ratio of the number of tissue-specific alternative splices observed in a tissue divided by the total number of ESTs observed in that tissue, normalized to have an average value of 1 (see text).
Figure 4
Figure 4
Kidney-specific alternative splicing of WNK1. (A) Genomic structure of WNK1. The genomic segment spanning WNK1 is represented by a horizontal line and exons by numbered vertical lines. Pink vertical lines indicate the alternative exons, IVa, IX, XI, XII and XXVI. (B) Gene structure for exons IV–VIII of the WNK1 gene. Exons are shown as boxes and colors show alternative exons. Splice a is specific to kidney. The putative in-frame stop codon UGA and start codon AUG are indicated. (C) The two alternative forms of WNK1 mRNA inferred from the expressed sequence data and the schematic representation of WNK1 protein sequences. The conserved kinase domain, two coiled-coil (CC) domains and the corresponding protein regions of mRNA forms are indicated. Three amino acids (K233, C250 and D368) that are required for the kinase activity of WNK1 (48) are marked by flags on the WNK1 protein.
Figure 5
Figure 5
Brain-specific alternative splicing of CDC42. (A) Genomic structure of the CDC42 gene. Exons are shown as boxes and colors show alternative exons. Splice a is specific to brain. (B) The two alternative forms of CDC42 mRNA inferred from the expressed sequence data. The protein coding region is indicated by an arrow beneath each form. (C) Alignment between the protein sequences encoded by the alternative exons VI and VII of CDC42. Conserved amino acids are in bold. The dilysine motif is indicated in red and the stop codons by asterisks.
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