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Canadian Bioinformatics Workshops
www.bioinformatics.ca
Module #: Title of Module
2
Module 4
Analyzing gene list function and
associations
Quaid Morris
Place an image representing the talk here
http://morrislab.med.utoronto.ca
Overview
• Extending gene lists using functional
associations
• Sources of functional association
• GeneMANIA
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Extending Gene Lists
• Given a gene list, find other similar genes
– Gene list defines the query and the “function” of interest
• Query: complex or pathway components
– Result: additional members
• Query: kinases
– Result: other kinases and related genes
• Query: genes affected in RNAi screen
– Result: other genes that may affect phenotype
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Network-Based Gene Function Prediction
• Genes of similar sequence often have similar function
• Unknown gene similar to known gene likely to have
similar function (annotation transfer)
• Guilt-by-association principle
• Many other similarity measures for genes (e.g. colocalization)
Fraser AG, Marcotte EM - A probabilistic
view of gene function - Nat Genet. 2004
Jun;36(6):559-64
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Functional association networks to predict
gene function
Microarray expression data
Co-expression network
Cell cycle
CDC3
CLB4
CDC16
UNK1
RPT1
RPN3
RPT6
Eisen et al (PNAS 1998)
UNK2
Protein degradation
Fraser AG, Marcotte EM - A probabilistic view of gene function - Nat Genet. 2004 Jun;36(6):559-64
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Predicting Gene Function Using a Network
Is gene X involved in cell cycle regulation?
+
CDC3
+
CDC16
CLB4
+
?
Labelled
examples
RPT1
-
UNK1
-
Classification
algorithm
UNK2
e.g. co-expression ?
UNK3
Module 4
UNK1
UNK2
UNK3
0.9
0.1
0.05
RPN3
?
RPT6
Discriminant
value
Discriminant value: a value you
can use to rank the genes
according to certainty or
threshold to classify genes
bioinformatics.ca
Predicting Gene Function Using a Network
Is gene X involved in cell cycle regulation?
+
CDC3
+
CDC16
CLB4
+
?
Labelled
examples
RPT1
-
UNK1
-
kNN,SVM,
LabelProp
UNK2
e.g. co-expression ?
UNK3
Module 4
UNK1
UNK2
UNK3
0.9
0.1
0.05
RPN3
?
RPT6
Discriminant
value
Discriminant value: a value you
can a) use to rank the genes
according to certainty and b)
threshold to classify genes
bioinformatics.ca
Label propagation vs guilt-by-association
CDC48
-1 …………....+1
MCA1
Discriminant
Value
CPR3
TDH2
Guilt-by-association
Label propagation algorithm
CDC48
MCA1
CDC48
CPR3
TDH2
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MCA1
CPR3
TDH2
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Types of functional associations
•
•
•
•
Molecular Interactions (i.e. physical interactions)
Regulatory Interactions (e.g. ChIP-chip binding)
Genetic Interactions (e.g. synthetic lethality)
Similarity relationships
–
–
–
–
–
–
–
Co-expression
Protein sequence (e.g. BLAST –log(E-value))
Domain architecture
Phylogenetic profiles
Gene neighborhood**
Gene fusion**
…
** most useful for bacterial genes
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Problem: genes are multi-function
• Gene function could be a/the:
–
–
–
–
–
–
Biological process,
Biochemical/molecular function,
Subcellular/Cellular localization,
Regulatory targets,
Temporal expression pattern,
Phenotypic effect of deletion.
Some networks may be better for some
types of gene function than others
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Query-specific weights for multifaceted
functional queries
w1 x
Cell
cycle
weights
w2 x
CDC27
CDC23
APC11
UNK1
+
+
Genetic
Tong et al. 2001
RAD54
XRS2
DNA
repair
UNK2
MRE11
w3 x
Co-complexed
Jeong et al 2002
=
Co-expression
June 24, 2009
The GeneMANIA project
Pavlidis et al, 2002,
Lanckriet et al, 2004
Mostafavi et al, 2008
13
GeneMANIA in the MouseFunc contest
“Test” benchmark: Predicting held-out genes
One of GeneMANIA’s two entries
had the best area under the
ROC curve in every category
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Sara Mostafavi
GeneMANIA performance on yeast
 More error
Slower 
GeneMANIA on 15 networks
GeneMANIA label
propagation on bioPIXIE*
Probabilistic graph search* on bioPIXIE*
GeneMANIA on 5 networks
TSS** on 5 networks
Mostafavi et al, 2008
* Myers et al, 2005
** Tsuda et al, 2005
15
GeneMANIA Prediction Server
http://www.genemania.org or http://qa.genemania.org
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GeneMANIA network data sources
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GeneMANIA Cytoscape Plugin
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Other prediction servers
• STRING (http://string-db.org/)
• Funcoup (http://funcoup.sbc.su.se/)
• FunctionalNet (http://www.functionalnet.org)
• bioPIXIE (http://pixie.princeton.edu)
• MouseNet (http://mousenet.princeton.edu/)
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Chemogenomics
• STITCH: Chemical-Protein Interactions
• http://stitch.embl.de/
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What Have We Learned?
• Network-based gene function prediction
– Guilt-by-association principle
• used to predict gene function using functional association networks
– Many types of functional associations exist
• Can be combined intelligently to optimize prediction accuracy
– Convenient software available: GeneMANIA
– Emerging area: chemical genomics gene function prediction
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Please follow along lab display on the
wiki
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