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Oncogene. 2004 Apr Identification of alternative spliced mRNA variants related to cancers by genome-wide ESTs alignment KIM DAE SOO MPL Alternative splicing Form BIOINFORMATICS MPL BIOINFORMATICS MPL Abstract Alternative splicing of mRNAs by analysing the exon linkage relationship by alignment of ESTs to the genome sequence Little effort has been made to investigate the relationship between cancers and alternative splicing Alternative splicing assembler(ASA) Of 4322 genes screened,3498(81%) were observed with at least one alternative splicing variants. Using Fisher’s test, alternative splicing variants BIOINFORMATICS MPL Introduction About 45% of the human EST sequence are derived from cancer cells. Alternative splicing is an important mechanism in higher eukaryotes for producing proteomics complexity Approximately 30-60% genes are alternative splicing as estimated by genomically aligned ESTs Human could conceivably produce hundreds of thousands of different proteins by the estimated 35,000 genes Alternative splicing of pre-mRNA is a versatile mechanism for regulating gene function at the post-transcription level BIOINFORMATICS MPL Alternative splicing defect as indicated by a survey of mutations in splicing junctions. A total of 26812 alternative spliced variants from 4322 genes were included in the database 2149 variants from 1827 genes were predicted as cancer associated. BIOINFORMATICS MPL Results ASA was created to identify alternative splicing of human gene transcripts 52 genes from alternative splicing database ,all having previously reported alternative splicing isoforms. Only four EST hits were available on the average for these 6 genes ,202 EST hits could be found for the other 46 genes ASA gives a false negative result of 12 % (about 88% of alternatively splicing genes) SpliceNest,PALS,HASDB which have false negative rates of 15,35 and 38% BIOINFORMATICS MPL BIOINFORMATICS MPL EST sequences might be contaminated by genomic sequence, vector sequences and chimaeric cDNA clone Randomly selected 82 splicing variants from 67 genes compared these variants with the NR db 26%(21 out of 82) variants found at least one reported mRNA sequences selected 13 variants ;RT-PCR (11 of 13 variants were confirmed by RT-PCR) BIOINFORMATICS MPL BIOINFORMATICS MPL Analysis of the alternative spliced variants and their tissue distribution in BASD A total of 4322 reference sequences were screened and 3490(81%) reference sequences were predicted as alternative spliced ,producing 26,812 splicing variants. On average six splicing variants were observed for each reference sequences. 87% variants contained less then 16 EST ,and 58% were represented by the EST singletons. If the singletons were excluded from the database, then only 66% genes were alternative spliced BIOINFORMATICS MPL A total of 6593 libraries were left and classified into 293 tissue types (NCBI EST data) A sample of 127 random genes was used to analysis the tissue distribution of alternative splicing Large fraction of splicing variants are tissue specific BIOINFORMATICS MPL BIOINFORMATICS MPL Identification of cancer-associated splicing variants about 35% splicing variants were detected exclusively in cancer tissues 29% were only detected in normal tissues This implies that new splicing variants might be generated during carcinogenesis This result supports the observation that during carcinogenesis not only is the expression profile affected but the splicing Patten BIOINFORMATICS MPL This 383 genes of variants will have a relatively higher confidence of cancer relationship. About 85% cancer related variants had more than 16 ESTs About 43% of cancer specific variants were related to more than two kinds of cancer types BIOINFORMATICS MPL BIOINFORMATICS MPL BIOINFORMATICS MPL BIOINFORMATICS MPL Discussion We constructed BASD to search for splicing variants of gene transcripts especially those associated with cancer These single EST supported variants in mining genomic information Our work presents a genomic view of the relationship between cancer and alternative splicing. BIOINFORMATICS MPL