MiDReG: Mining Developmentally Regulated Genes

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MiDReG Mining Developmentally Regulated Genes

• Debashis Sahoo
• PhD, Electrical Engineering, Stanford University
• Joint work with The Weissman Lab

Integrative Cancer Biology Program, Stanford
University
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Perspective
Database of Dynamic ranges of each probesets
RMA
4878 Human Microarrays 2167 Mouse Microarrays
Poster 38 Jun Seita
BooleanNet
MiDReG
Predicts developmentally regulated genes
Database of Boolean implications
Debashis Poster
MiDReG
Identifies a branchpoint between B and T cell
development
Poster 17 Matt Inlay
Biology of HSC differentiation
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Motivation

• Hard to discover using other approaches
• Genetics
• Biochemistry
• These genes carry out important functions
• Development and differentiation
• Surface markers are easy to study

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BooleanNet
Get data
GEO
Edgar et al. 02
Normalize
RMA
Irizarry et al. 03
Determine thresholds
Discover Boolean relationships
Biological interpretation
Sahoo et al. Genome Biology 2008
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Determine threshold

• A threshold is determined for each gene.
• The arrays are sorted by gene expression
• StepMiner is used to determine the threshold

High
CDH expression
Low
Sorted arrays
Sahoo et al. 07
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Discovering Boolean Implications

• Analyze pairs of genes.
• Analyze the four different quadrants.
• Identify sparse quadrants.
• Record the Boolean relationships.
• ACPP high ? GABRB1 low
• GABRB1 high ? ACPP low

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4
GABRB1
1
3
ACPP
Sahoo et al. Genome Biology 2008
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Six Boolean Implications
Sahoo et al. Genome Biology 2008
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Prediction of Developmentally Regulated Genes
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Computational Discovery of Human B Cell Precursors
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qPCR Results
Test Median1 lt Median2 10/14 pass (FDR 14)




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More B Cell Precursors
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Validation
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Analysis of Predicted Genes

• Total number of genes predicted 62
• 33 genes have been knocked out in mice.
  Literature
• 18 genes have defects in B cell function and B
  cell differentiation.
• 2 genes are known prognostic markers of B cell
  lymphomas WASPIP and GCET2.

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Conclusion

• MiDReG uses Boolean implications to predict genes
  related to B cell development
• Knockouts of the predicted genes have defects in
  B cell function and differentiation
• MiDReG can be directly applied to other less
  well-characterized developmental pathway

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Acknowledgements
David L. Dill

• Sylvia K. Plevritis
• Irving L. Weissman
• The Weissman Lab
• Deepta, Jun, Matt

• Robert Tibshirani

Funding ICBP Program (NIH grant
5U56CA112973-02)
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The END
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Statistical Tests

• Compute the expected number of points under the
  independence model
• Compute maximum likelihood estimate of the error
  rate

nAlow (a00 a01), nBlow (a00 a10) total
a00 a01 a10 a11, observed a00 expected
(nAlow/ total nBlow/ total) total