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Sven Bergmann Department of Medical Genetics, UNIL & Swiss Institute of Bioinformatics

WP8: Computational analysis of beta-cell modular organization. EuroDia 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.

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Sven Bergmann Department of Medical Genetics, UNIL & Swiss Institute of Bioinformatics

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  1. WP8:Computational analysis of beta-cell modular organization EuroDia Meeting Lund, 23-25 February 2009 Sven Bergmann Department of Medical Genetics, UNIL & Swiss Institute of Bioinformatics http://serverdgm.unil.ch/bergmann

  2. Iterative Signature Algorithm • Unsupervised large-scale data analysis tool • Modularizes the expression matrix • Reduction of complexity • Allows for easy data integration • Interactive webtool

  3. Modular Analysis • A block of the reordered expression matrix • Genes and samples have scores • Captures differential co-expression Transcription Module

  4. Non-modular Analysis

  5. Modular Analysis

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

  7. The Data Set • Coming from WP2, Frans Schuit's group. • C57bl6 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 mouse4302 array

  8. Batch and Tissue Effects Pituary gland Islets

  9. Spearman Rank correlation between 75 Affy mouse 430 2.0 arrays TISSUE (n arrays)‏ High Fat Diet (5)‏ 1 Islets 2 Standard Diet (4)‏ 3 Pancreatic acini (3)‏ 4 Adrenal (3)‏ 5 Brain (3)‏ 6 ES cells (3)‏ 7 Adipose tissue (3)‏ 8 Eye (3)‏ 9 Heart (3)‏ 10 Small intestine (3)‏ 11 Hypothalamus (3)‏ 12 Liver (3)‏ 13 Lung(3)‏ 14 Kidney (3)‏ 15 Parotis gland (3)‏ 16 Spleen (3)‏ 17 Seminal vesicles (3)‏ 18 Testis (3)‏ 19 Thymus (3)‏ 20 Diafragm (3)‏ 21 Skeletal muscle (4)‏ 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

  10. Very preliminaryModular 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://www2.unil.ch/cbg/Eurodia/isa3-html/maintable.html

  11. 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

  12. Pancreas-Specific Modules • Genes: Gcg, Iapp, Abcc8, Scn9a, Prss2, Pnlip, Ela3, Rab37, Cuzd1, Pnliprp2, Clps, Rnase1, Asb6, Ctrb1, BC039632, B830017H08Rik, A930021C24Rik, 2210010C04Rik, 1810049H19Rik

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

  14. Islet specific GO enrichment P-value # Category 5.03e-7 49 digestion 1.25e-12 10 extracellular region 3.18e-5 20 mitochondrion 1.44e-4 25 proton-transporting ATP synthase complex, catalytic core F(1)‏ 1.04e-6 64 serine-type endopeptidase activity1.49e-4 151 endopeptidase activity 3.33e-4 16 structural constituent of ribosome

  15. Islet specific KEGG enrichment P-value # Category 4.37e-6 16 Ribosome 3.26e-4 155 Oxidative phosphorylation

  16. Islet specific miRNAs P-value # Category 6.65e-3 892 miR-30 family

  17. Islets-only Analysis

  18. 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://www2.unil.ch/cbg/Eurodia/isa5-html/maintable.html

  19. 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

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

  21. 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 KU Leuven: Leentje van Lommel Frans Schuit Thanks to EuroDia! http://serverdgm.unil.ch/bergmann

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

  23. High Fat Diet Islets • Intersection of module #41 and “Serine-type endopeptidase activity”, GO molecular function category

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