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Introduction to DNA Microarrays: Functional Mining of Array 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 mfmiles@vcu.edu 225-4054. Tertiary Analysis: Connecting Function with Expression Patterns.

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Introduction to DNA Microarrays: Functional Mining of Array Patterns

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  1. 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 mfmiles@vcu.edu 225-4054

  2. 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

  3. CARS: A Curated Annotation Database Tool

  4. 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

  5. Microarray Analysis of Gene Expression in Prefrontal Cortex of Schizophrenics Mirnics et al., Neuron 28:53, 2000

  6. Functional Hierarchy Statistics in Alcoholic Brain Tissue (Frontal Cortex) Distribution of Expressed Genes across Seven Frontal Cortex Comparisons Percent of Change ALL Frontal MYEL GLU PSYN APOP Cell cycle AlcRes (44029) (120) (50) (511) (618) (752) (733) <=-1.9 0.7 4.2 2.0 1.2 0.3 1.1 1.4 -1.6 to -1.89 1.9 8.3 6.0 2.0 1.5 2.7 3.3 -1.59 to 1.59 94.9 75.8 86.0 93.9 96.0 94.7 92.0 1.6 to 1.89 1.8 4.2 6.0 2.5 2.1 1.2 2.3 >=1.9 0.7 7.5 0.0 0.4 0.2 0.4 1.1 Chi-square, p< NA <<0.0001 0.0002 0.95 0.94 0.93 0.72 Courtesy of Dr. Adron Harris, UT at Austin

  7. Non-biased (semi) Functional Group Analysis: GenMAPP

  8. 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

  9. Efforts to Integrate Diverse Biological Databases with Expression Information: PubGen www.PubGen.org

  10. 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

  11. Expression of Aldh9a1 Across BxD RI Lines

  12. WebQTL Allows Definition of Genetic “Linkage” for Expression Patterns

  13. 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)

  14. 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)

  15. Correlation in Expression Profiles of Drugs/Genes Affecting Same Pathways cup5 and vma8, components of H+/ATPase complex Unrelated gene mutants HMG CoA-reductase mutant vs. lovastatin, an inhibitor of HMG2 Red symbols = significant change (p<0.05) in both treatments Hughes et al. Cell 102:109-126 (2000)

  16. Assigning Function to Uncharacterized Genes by Expression Profiles Hughes et al. Cell 102:109-126 (2000)

  17. Expression Profiling Prot-Prot Interactions BioMed Lit Relations Expression Networks Ontology HomoloGene Genetics Pharmacology Behavior

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