1. Expression Modules Brian S. Yandell (with slides from Steve Horvath, UCLA, and Mark Keller, UW-Madison)

2. Weighted models for insulin Detected by scanone Detected by Ping’s multiQTL model tissue# transcripts Islet1984 Adipose605 Liver485 Gastroc404 # transcripts that match weighted insulin model in each of 4 tissues:

3. insulin main effects Ping Wang How many islet transcripts show this same genetic dependence at these loci? Chr 9Chr 12Chr 14 Chr 16Chr 17Chr 19 Chr 2

4. Expression Networks Zhang & Horvath (2005) www.genetics.ucla/edu/labs/horvath/CoexpressionNetwork organize expression traits using correlation adjacency connectivity topological overlap

5. Using the topological overlap matrix (TOM) to cluster genes – modules correspond to branches of the dendrogram TOM plot Hierarchical clustering dendrogram TOM matrix Module: Correspond to branches Genes correspond to rows and columns

6. module traits highly correlated adjacency attenuates correlation can separate positive, negative correlation summarize module – eigengene – weighted average of traits relate module – to clinical traits – map eigengene www.genetics.ucla/edu/labs/horvath/CoexpressionNetwork

7. advantages of Horvath modules emphasize modules (pathways) instead of individual genes – Greatly alleviates the problem of multiple comparisons – ~20 module comparisons versus 1000s of gene comparisons intramodular connectivity k i finds key drivers (hub genes) – quantifies module membership (centrality) – highly connected genes have an increased chance of validation module definition is based on gene expression data – no prior pathway information is used for module definition – two modules (eigengenes) can be highly correlated unified approach for relating variables – compare data sets on same mathematical footing scale-free: zoom in and see similar structure

8. modules for 1984 transcripts with similar genetic architecture as insulin contains the insulin trait Ping Wang

9. Islet – modules Insulin trait chromosomes 17 2 16 14 19 12 9

10. Islet – enrichment for modules chromosomes ModulePvalueQvalueCountSizeTerm BLUE0.00050.0463301068biosynthetic process 0.00060.047018511cellular lipid metabolic process 0.00090.050711241lipid biosynthetic process 0.00120.059319590lipid metabolic process GREEN0.00080.0457476phosphate transport 0.00550.0970220intermediate filament-based process 0.00560.097010707ion transport PURPLE0.00110.016572769 nucleobase, nucleoside, nucleotide and nucleic acid metabolic process BLACK0.00780.0138268sensory perception of sound MAGENTA2.54E-050.00117313cell cycle process 0.00010.00405179microtubule-based process 0.00040.00405225mitotic cell cycle 0.00050.00405228M phase 0.00060.00405239cell division 0.00090.00415266cell cycle phase 0.00110.00414162mitosis 0.00120.00414163M phase of mitotic cell cycle YELLOW0.00260.06757281cell projection organization and biogenesis 0.00260.06757281cell part morphogenesis 0.00260.06757281cell projection morphogenesis RED0.00170.0619213steroid hormone receptor signaling pathway 0.00260.06195200reproductive process BROWN0.00570.1442496response to pheromone TURQUOISE0.00020.083017279enzyme linked receptor protein signaling pathway 0.00030.083010115morphogenesis of an epithelium 0.00030.0830757morphogenesis of embryonic epithelium 0.00040.0830401021anatomical structure morphogenesis PINK0.00040.0608214vesicle organization and biogenesis 0.00920.06124384regulation of apoptosis Insulin

11. www.geneontology.org ontologies – Cellular component (GOCC) – Biological process (GOBP) – Molecular function (GOMF) hierarchy of classification – general to specific – based on extensive literature search, predictions prone to errors, historical inaccuracies