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Identification of alternative spliced mRNA variants related to cancers by genome-wide ESTs alignment

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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. – PowerPoint PPT presentation

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Title: Identification of alternative spliced mRNA variants related to cancers by genome-wide ESTs alignment


1
Identification of alternative spliced mRNA
variants related to cancers by genome-wide ESTs
alignment
Oncogene. 2004 Apr
  • KIM DAE SOO

2
Alternative splicing Form
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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 Fishers test, alternative splicing
    variants

5
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

6
  • 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.

7
ResultsASA 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

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  • 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)

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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

12
  • 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

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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

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  • 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

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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.
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