Transcript Tertiary Analysis: Connecting Function with Expression Patterns

Introduction to DNA
Microarrays: Functional Mining
of Array Patterns
Michael F. Miles, M.D., Ph.D.
Depts. of Pharmacology/Toxicology and Neurology and the
Center for Study of Biological Complexity
[email protected]
225-4054
Tertiary Analysis: Connecting
Function with Expression Patterns
• Annotation
– UniGene/Swiss-Prot, SOURCE, CARS
• Biased functional assessment
– Functional group interrogation
Manual, GenMAPP, GeneSpring
• Non-biased functional queries
– PubGen
– MAPPFinder, DAVID/Ease, GEPAS, others
– Cytoscape
• Overlaying genomics and genetics
– WebQTL
CARS: A Curated Annotation Database Tool
Tertiary Analysis: Connecting
Function with Expression Patterns
• Annotation
– UniGene/Swiss-Prot, SOURCE, CARS
• Biased functional assessment
– Functional group interrogation
• Manual, GenMAPP, GeneSpring
• Non-biased functional queries
– PubGen
– MAPPFinder, DAVID/Ease, GEPAS, others
– Cytoscape
• Overlaying genomics and genetics
– WebQTL
Microarray Analysis of Gene Expression in
Prefrontal Cortex of Schizophrenics
Mirnics et al., Neuron 28:53, 2000
Functional Hierarchy Statistics in Alcoholic Brain Tissue
(Frontal Cortex)
Distribution of Expressed Genes across Seven Frontal Cortex Comparisons
Percent of Change
<=-1.9
-1.6 to -1.89
-1.59 to 1.59
1.6 to 1.89
>=1.9
Chi-square, p<
ALL Frontal
(44029)
MYEL
(120)
GLU
(50)
PSYN
(511)
APOP
(618)
Cell cycle
(752)
AlcRes
(733)
0.7
1.9
94.9
1.8
0.7
NA
4.2
8.3
75.8
4.2
7.5
<<0.0001
2.0
6.0
86.0
6.0
0.0
0.0002
1.2
2.0
93.9
2.5
0.4
0.95
0.3
1.5
96.0
2.1
0.2
0.94
1.1
2.7
94.7
1.2
0.4
0.93
1.4
3.3
92.0
2.3
1.1
0.72
Courtesy of Dr. Adron Harris, UT at Austin
Non-biased (semi) Functional
Group Analysis: GenMAPP
Tertiary Analysis: Connecting
Function with Expression Patterns
• Annotation
– UniGene/Swiss-Prot, SOURCE, CARS
• Biased functional assessment
– Functional group interrogation
• Manual, GenMAPP, GeneSpring
• Non-biased functional queries
– PubGen
– MAPPFinder, DAVID/Ease, GEPAS, others
– Cytoscape
• Overlaying genomics and genetics
– WebQTL
Efforts to Integrate Diverse Biological Databases
with Expression Information: PubGen
www.PubGen.org
Tertiary Analysis: Connecting
Function with Expression Patterns
• Annotation
– UniGene/Swiss-Prot, SOURCE, CARS
• Biased functional assessment
– Functional group interrogation
• Manual, GenMAPP, GeneSpring
• Non-biased functional queries
– PubGen
– MAPPFinder, DAVID/Ease, GEPAS, others
– Cytoscape
• Overlaying genomics and genetics
– WebQTL
QuickTime™ and a TIFF (Uncompressed) decompressor are needed to see this picture.
Expression of Aldh9a1
Across BxD RI Lines
QuickTime™ and a TIFF (Uncompressed) decompressor are needed to see this picture.
WebQTL Allows Definition of Genetic
“Linkage” for Expression Patterns
QuickTime™ and a TIFF (Uncompressed) decompressor are needed to see this picture.
QuickTime™ and a TIFF (Uncompressed) decompressor are needed to see this picture.
QuickTime™ and a TIFF (Uncompressed) decompressor are needed to see this picture.
Expression
Profiling:
“It is possible that the expression
profile could serve as a universal
phenotype … Using a
comprehensive database of
reference profiles, the pathway(s)
perturbed by an uncharacterized
mutation would be ascertained by
simply asking which expression
patterns in the database its profile
most strongly resembles … it
should be equally effective at
determining consequences of
pharmaceutical treatments and
disease states”
Hughes et al. Cell 102:109-126 (2000)
Use of Expression Profile “Compendium” to
Characterize Gene or Drug Function
Key features:
established error model
profiled large number of mutants/drugs under highly controlled conditions
statistical treatment of expression patterns
verified array results with biochemical/phenotypic assays
Hughes et al. Cell 102:109-126 (2000)
Correlation in Expression Profiles of
Drugs/Genes Affecting Same Pathways
cup5 and vma8,
components of
Unrelated gene
mutants
H+/ATPase complex
Red symbols = significant change (p<0.05) in both treatments
HMG CoAreductase mutant
vs. lovastatin, an
inhibitor of
HMG2
Hughes et al. Cell 102:109-126 (2000)
Assigning Function to Uncharacterized Genes by
Expression Profiles
Hughes et al. Cell 102:109-126 (2000)
Expression Profiling
Prot-Prot
Interactions
BioMed Lit
Relations
Expression Networks
Ontology
HomoloGene
Genetics
Pharmacology
Behavior