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!
