TISA: tissue-specific alternative splicing in human and mouse genes.

Alternative splicing (AS) is a mechanism by which multiple transcripts are produced from a single gene and is thought to be an important mechanism for tissue-specific expression of transcript isoforms. Here, we report a novel graphing method for transcript reconstruction and statistical prediction of tissue-specific AS. We applied three selection steps to generate the splice graph and predict the transcript isoforms: (i) a custom scoring rule for exon/intron sets, (ii) binomial statistics for selecting valid alternative splicing with a frequency of at least 1% for the predominant form and (iii) evaluation of transcript structure. We obtained 97 286 and 66 022 valid transcripts from 26 143 human and 27 741 mouse genes, respectively. In addition, we discovered 33 481 AS events for nine types of AS patterns in human. The statistical significance of tissue specificity for each gene, transcript and AS event was assessed based on EST tissue information, followed by a multiple testing correction procedure. In human, 12 711 genes, 16 016 transcripts and 1035 AS events were predicted to be tissue-specific (false discovery rate <0.01). This information on genes, transcript structures, AS events and their tissue specificities in human and mouse are freely accessible on the TISA website (http://tisa.kribb.re.kr/AGC/).

[1]  Christopher J. Lee,et al.  A genomic view of alternative splicing , 2002, Nature Genetics.

[2]  P. Fehlbaum,et al.  A microarray configuration to quantify expression levels and relative abundance of splice variants , 2005, Nucleic acids research.

[3]  A. Kornblihtt,et al.  Multiple links between transcription and splicing. , 2004, RNA.

[4]  L. Bracco,et al.  The relevance of alternative RNA splicing to pharmacogenomics. , 2003, Trends in biotechnology.

[5]  Yi Xing,et al.  The multiassembly problem: reconstructing multiple transcript isoforms from EST fragment mixtures. , 2004, Genome research.

[6]  Jorng-Tzong Horng,et al.  ProSplicer: a database of putative alternative splicing information derived from protein, mRNA and expressed sequence tag sequence data , 2003, Genome Biology.

[7]  David States,et al.  Selecting for functional alternative splices in ESTs. , 2002, Genome research.

[8]  T. Cooper,et al.  Finding signals that regulate alternative splicing in the post-genomic era , 2002, Genome Biology.

[9]  G. Rubin,et al.  A computer program for aligning a cDNA sequence with a genomic DNA sequence. , 1998, Genome research.

[10]  Tin Wee Tan,et al.  DEDB: a database of Drosophila melanogaster exons in splicing graph form , 2004, BMC Bioinformatics.

[11]  W. Gish,et al.  Gene structure prediction and alternative splicing analysis using genomically aligned ESTs. , 2001, Genome research.

[12]  Thangavel Alphonse Thanaraj,et al.  ASD: the Alternative Splicing Database , 2004, Nucleic Acids Res..

[13]  W. J. Kent,et al.  BLAT--the BLAST-like alignment tool. , 2002, Genome research.

[14]  Ron Shamir,et al.  A non-EST-based method for exon-skipping prediction. , 2004, Genome research.

[15]  Y. Benjamini,et al.  THE CONTROL OF THE FALSE DISCOVERY RATE IN MULTIPLE TESTING UNDER DEPENDENCY , 2001 .

[16]  Steffen Heber,et al.  The Alternative Splicing Gallery (ASG): bridging the gap between genome and transcriptome. , 2004, Nucleic acids research.

[17]  P Bork,et al.  EST comparison indicates 38% of human mRNAs contain possible alternative splice forms , 2000, FEBS letters.

[18]  Martin Vingron,et al.  Genome wide identification and classification of alternative splicing based on EST data , 2004, Bioinform..

[19]  Namshin Kim,et al.  ECgene: genome-based EST clustering and gene modeling for alternative splicing. , 2005, Genome research.

[20]  Simon Cawley,et al.  HMM sampling and applications to gene finding and alternative splicing , 2003, ECCB.

[21]  Eduardo Eyras,et al.  ESTGenes: alternative splicing from ESTs in Ensembl. , 2004, Genome research.

[22]  T. Maniatis,et al.  Common themes in the function of transcription and splicing enhancers. , 1997, Current opinion in cell biology.

[23]  Ron Shamir,et al.  Accurate identification of alternatively spliced exons using support vector machine , 2005, Bioinform..

[24]  J. Claverie,et al.  The significance of digital gene expression profiles. , 1997, Genome research.

[25]  A. Krainer,et al.  Listening to silence and understanding nonsense: exonic mutations that affect splicing , 2002, Nature Reviews Genetics.

[26]  Bosiljka Tasic,et al.  Alternative pre-mRNA splicing and proteome expansion in metazoans , 2002, Nature.

[27]  Christopher J. Lee,et al.  Genome-wide detection of alternative splicing in expressed sequences of human genes , 2001, Nucleic Acids Res..

[28]  Christopher J. Lee.  Generating Consensus Sequences from Partial Order Multiple Sequence Alignment Graphs , 2003, Bioinform..

[29]  B. Frey,et al.  Revealing global regulatory features of mammalian alternative splicing using a quantitative microarray platform. , 2004, Molecular cell.

[30]  Stefan Stamm,et al.  Signals and their transduction pathways regulating alternative splicing: a new dimension of the human genome. , 2002, Human molecular genetics.

[31]  Gene W. Yeo,et al.  Variation in alternative splicing across human tissues , 2004, Genome Biology.

[32]  Christopher J. Lee,et al.  Genome-wide detection of tissue-specific alternative splicing in the human transcriptome. , 2002, Nucleic acids research.

[33]  M. Garcia-Blanco,et al.  Alternative splicing in disease and therapy , 2004, Nature Biotechnology.

[34]  B. Zhang,et al.  GeneKeyDB: A lightweight, gene-centric, relational database to support data mining environments , 2004, BMC Bioinformatics.

[35]  May D. Wang,et al.  GoMiner: a resource for biological interpretation of genomic and proteomic data , 2003, Genome Biology.

[36]  J. Castle,et al.  Genome-Wide Survey of Human Alternative Pre-mRNA Splicing with Exon Junction Microarrays , 2003, Science.

[37]  Gunnar Rätsch,et al.  RASE: recognition of alternatively spliced exons in C.elegans , 2005, ISMB.

[38]  S. Brenner,et al.  Evidence for the widespread coupling of alternative splicing and nonsense-mediated mRNA decay in humans , 2002, Proceedings of the National Academy of Sciences of the United States of America.