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

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:

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

Expression Networks Zhang & Horvath (2005) organize expression traits using correlation adjacency connectivity topological overlap

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

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

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

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

Islet – modules Insulin trait chromosomes

Islet – enrichment for modules chromosomes ModulePvalueQvalueCountSizeTerm BLUE biosynthetic process cellular lipid metabolic process lipid biosynthetic process lipid metabolic process GREEN phosphate transport intermediate filament-based process ion transport PURPLE nucleobase, nucleoside, nucleotide and nucleic acid metabolic process BLACK sensory perception of sound MAGENTA2.54E cell cycle process microtubule-based process mitotic cell cycle M phase cell division cell cycle phase mitosis M phase of mitotic cell cycle YELLOW cell projection organization and biogenesis cell part morphogenesis cell projection morphogenesis RED steroid hormone receptor signaling pathway reproductive process BROWN response to pheromone TURQUOISE enzyme linked receptor protein signaling pathway morphogenesis of an epithelium morphogenesis of embryonic epithelium anatomical structure morphogenesis PINK vesicle organization and biogenesis regulation of apoptosis Insulin

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