WP 8 Computational analysis of betacell modular organization

WP 8: Computational analysis of beta-cell modular organization Euro. Dia Meeting Lund, 23 -25 February 2009 Sven Bergmann Department of Medical Genetics, UNIL & Swiss Institute of Bioinformatics http: //serverdgm. unil. ch/bergmann

Iterative Signature Algorithm Unsupervised largescale data analysis tool Modularizes the expression matrix Reduction of complexity Allows for easy data integration Interactive webtool

Modular Analysis Transcription Module A block of the reordered expression matrix Genes and samples have scores Captures differential coexpression

Non-modular Analysis

Modular Analysis

Modular Analysis of Multi-tissue Gene Expression Data Gábor Csárdi and Sven Bergmann Computational Biology Group, Department of Medical Genetics, University of Lausanne, Switzerland

The Data Set Coming from WP 2, Frans Schuit's group. C 57 bl 6 mice, plus 7 S/A islet samples 23 different tissues: adrenal gland, bone marrow, brain, diaphragma, ES cells, eye, fat, fetal, gastrocnemius muscle, heart, islet, kidney, liver, lung, ovary, parotis gland, pituitary gland, placenta, seminal vesicles, small intestine, spleen, testis, thymus. 3 -5 samples/tissue, 89 altogether 19 islet samples, 8 on high fat diet After filtering based on variance: 14, 540 of 45, 101 probesets left on the mouse 4302 array

Batch and Tissue Effects Pituary gland Islets

Spearman Rank correlation between 75 Affy mouse 430 2. 0 arrays TISSUE (n arrays) High Fat Diet (5) Islets Standard Diet (4) 1 Pancreatic acini (3) Adrenal (3) Brain (3) ES cells (3) Adipose tissue (3) Eye (3) Heart (3) Small intestine (3) Hypothalamus (3) Liver (3) Lung(3) Kidney (3) Parotis gland (3) Spleen (3) Seminal vesicles (3) Testis (3) Thymus (3) Diafragm (3) Skeletal muscle (4) 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 2 Pituitary gland (5) 22 Bone marrow (4) 23 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23

Very preliminary Modular Analysis Results 977 transcription modules were identified High enrichment by tissues, GO categories, KEGG pathways and transcription factors Condition plots Show tissue specific modules http: //www 2. unil. ch/cbg/Eurodia/isa 3 -html/maintable. html

Pancreas-Specific Modules (Islets + contaminating exocrine cells) Example: #49, 35 probes, 27 Entrez genes, 43 conditions, 19 islet samples with positive scores Many pancreas related genes

Pancreas-Specific Modules Genes: Gcg, Iapp, Abcc 8, Scn 9 a, Prss 2, Pnlip, Ela 3, Rab 37, Cuzd 1, Pnliprp 2, Clps, Rnase 1, Asb 6, Ctrb 1, BC 039632, B 830017 H 08 Rik, A 930021 C 24 Rik, 2210010 C 04 Rik, 1810049 H 19 Rik

Pancreas-specific Modules Module #49 Differentiates between islets and other tissues

Islet specific GO enrichment P-value 5. 03 e-7 # 49 Category digestion 1. 25 e-12 3. 18 e-5 1. 44 e-4 10 20 25 1. 04 e-6 1. 49 e-4 64 serine-type endopeptidase activity 151 endopeptidase activity 3. 33 e-4 16 extracellular region mitochondrion proton-transporting ATP synthase complex, catalytic core F(1) structural constituent of ribosome

Islet specific KEGG enrichment P-value 4. 37 e-6 3. 26 e-4 # Category 16 Ribosome 155 Oxidative phosphorylation

Islet specific mi. RNAs P-value 6. 65 e-3 # Category 892 mi. R-30 family

Islets-only Analysis

High Fat Diet Islets Running ISA on the 19 islet samples only Only 8, 288 probesets after filtering Module #41 differentiates between HF/LF diets best: http: //www 2. unil. ch/cbg/Eurodia/isa 5 -html/maintable. html

High Fat Diet Islets Condition scores significantly differ, p-value: 8. 5*10 -3 Significantly enriched for serine-type endopeptidase activity, p-value: 3*10 -12 Enriched for regulation by Trypsin GTF, p-value: 3*10 -14

High Fat Diet Islets Module #41 58 probes, 45 Entrez genes Two outliers

Acknowledgements UNIL CBG: Zoltán Kutalik Micha Hersch Aitana Morton Diana Marek Barbara Piasecka Bastian Peter Karen Kapur Alain Sewer Toby Johnson Armand Valsessia Gabor Csardi Sascha Dalessi Thanks to Euro. Dia! KU Leuven: Leentje van Lommel Frans Schuit http: //serverdgm. unil. ch/bergmann

High Fat Diet Islets Serine-type endopeptidase activity, GO molecular function category

High Fat Diet Islets Intersection of module #41 and “Serinetype endopeptidase activity”, GO molecular function category