sven bergmann department of medical genetics, unil & swiss institute of bioinformatics

Sven Bergmann Department of Medical Genetics, UNIL &

Swiss Institute of Bioinformatics

http://serverdgm.unil.ch/bergmann

WP8:Computational analysis of

beta-cell modular organization

EuroDia MeetingLund, 23-25 February 2009

Iterative Signature Algorithm

Unsupervised large-scale data analysis tool

Modularizes the expression matrix

Reduction of complexity Allows for easy

data integration Interactive webtool

Modular Analysis

A block of the reordered expression matrix

Genes and samples have scores

Captures differential co-expressionTranscription Module

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 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

Batch and Tissue Effects

Islets

Pituary gland

Spearman Rank correlation between 75 Affy mouse 430 2.0 arrays

High Fat Diet (5)

Standard Diet (4)

Pancreatic acini (3)Adrenal (3)

ES cells (3)Brain (3)

Eye (3)Adipose tissue (3)

Heart (3)

Hypothalamus (3)Small intestine (3)

Kidney (3)

Liver (3)Lung(3)

Parotis gland (3)Spleen (3)

Testis (3)Thymus (3)

Diafragm (3)

Pituitary gland (5)

Bone marrow (4)

Seminal vesicles (3)

Skeletal muscle (4)

1

2

3456789

101112131415161718192021

22

23

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23

Islets

TISSUE (n arrays)

Batch and Tissue Effects

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://www2.unil.ch/cbg/Eurodia/isa3-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, Abcc8, Scn9a, Prss2, Pnlip, Ela3, Rab37, Cuzd1, Pnliprp2, Clps, Rnase1, Asb6, Ctrb1,

BC039632, B830017H08Rik, A930021C24Rik, 2210010C04Rik, 1810049H19Rik,

Pancreas-specific Modules

Module #49 Differentiates

between islets and other tissues

Islet specific GO enrichment

P-value # Category

5.03e-7 49 digestion

1.25e-12 10 extracellular region3.18e-5 20 mitochondrion1.44e-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

Islet specific KEGG enrichment

P-value # Category

4.37e-6 16 Ribosome3.26e-4 155 Oxidative phosphorylation

Islet specific miRNAs

P-value # Category

6.65e-3 892 miR-30 family

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

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

High Fat Diet Islets

Serine-type endopeptidase activity, GO molecular function category

High Fat Diet Islets

Intersection of module #41 and “Serine-type endopeptidase activity”, GO molecular function category

Acknowledgements

http://serverdgm.unil.ch/bergmann

People: Zoltán KutalikMicha HerschAitana MortonDiana MarekBarbara PiaseckaBastian PeterKaren KapurAlain SewerToby JohnsonArmand ValsessiaGabor CsardiSascha Dalessi

Thanks to EuroDia!