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Transcript isoform entropy: proof of extensive disruption in cancerous tissues

Transcript isoform entropy: proof of extensive disruption in cancerous tissues. William Ritchie July 20 2007. Disruption of Alternative splicing in trans or cis elements. TRANS. CIS. Creation of a new isoform Disruption of expression levels. 1. 2. 3. 4.

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Transcript isoform entropy: proof of extensive disruption in cancerous tissues

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  1. Transcript isoform entropy: proof of extensive disruption in cancerous tissues William Ritchie July 20 2007

  2. Disruption of Alternative splicing in trans or cis elements TRANS CIS • Creation of a new isoform • Disruption of expression levels

  3. 1 2 3 4 Disruption of Alternative splicing leads to 2 types of deregulation 14 14 14 28 28 28 3 3 32 _ _ 8 • (p53, Rac1) (Bcl-xs/xl)

  4. 1 2 3 4 Disruption of Alternative splicing may lead to a third type of deregulation 14 14 14 16 28 28 28 17 3 3 32 16 _ _ 8 Expression pattern loss

  5. Entropy: Definition • Measure of disorder in a given system • Information theory: uncertainety of an outcome • Shannon’s entropy: • Given a variable X with probabilities P(xi) for a discrete set of events x1,…,xk

  6. Using shannon’s entropy to detect isoform deregulation 14 16 1 28 17 2 3 16 3 1.5 bits 3 bits = 2

  7. Using shannon’s entropy to detect isoform deregulation • Alternative splicing, polyadenylation (EBI, ATD), initiation (fantom3) • Consider events with 10 transcripts, 3 libraries • Consider events found in disease and normal tissue

  8. Entropy of alternative isoforms

  9. Correlation Entropy & proliferation ? • Link between cellular proliferation and entropy ? • Determining proliferation levels is tricky

  10. Determining a proliferation index Determining a proliferation signature w/ microarrays Stuart et al., 2003 Clusters of functionally related genes

  11. Correlation Entropy & proliferation !

  12. Functions affected by Entropy • 414 genes • Splicing machinery itself is subject to high Entropy

  13. Splice factors subject to higher AS rates (72% - 5.4 Vs 62% - 3.4) Enrichment in GO “Splicing” terms No significant enrichment in GO terms The enrichment in “splicing” terms is due to high levels of entropy

  14. Conclusion • Shannon’s entropy detects a loss of information in alternative splicing in cancerous tissues (not spurious isoforms) • High entropy gains correlate with high levels of proliferation • Splicing machinery itself might be the starting point of this deregulation

  15. A theory of generalized deregulation

  16. Thanks Daniel Gautheret Sam Granjeaud Denis Puthier Fafa Lopez Mr. Hide

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