An update on ongoing projects within Biorange SP3.2.2.1

Biorange Project Meeting

Leiden, September 15

Tim Hulsen

Biorange SP3.2.2

CoPub

Knowledge integration

ArrayExpress db

User

Xref db

Gene annotation throughapplications: PhyloPat,BioVenn, OrthoPath, CoPub

Overview

• PhyloPat• Published in BMC Bioinformatics (2006)• Update submitted to Nucleic Acids Res. Database issue

• BioVenn• Revised version submitted to BMC Genomics

• Orthologous networks & OrthoPath• Manuscript in preparation

• CoPub (Taverna workflows)• Published in Nucleic Acids Res. Web Server issue (2008)

PhyloPat - Introduction

• Phylogenetic patterns show the presence or absence of certain genes in a set of full genomes derived from different species

• PhyloPat allows the complete Ensembl gene database to be queried using phylogenetic patterns

• Published in september 2006, now new version with:• Ensembl v50

• Support of HGNC and EntrezGene IDs

• FASTA-format sequences of the members of a phylogenetic lineage

• Gene neighborhood view

• http://www.cmbi.ru.nl/phylopat

PhyloPat: Update to Ensembl v50

• 39 species, under which model organisms such as C. elegans, D. melanogaster, D. rerio, G. gallus, M. musculus, R. norvegicus, C. familiaris, M. mulatta, and human

• In total 814,936 genes

• In total 244,114 orthologous groups, created by clustering the orthologous gene pairs predicted by Ensembl

PhyloPat: Support of HGNC and EntrezGene IDs

• HGNC-Ensembl mapping for 29 species

• EntrezGene-Ensembl mapping for 18 species

Choose form four types of IDs

PhyloPat: FASTA-format sequences

“L”: Longest peptide sequences from this orthologous group (only the longest peptide per gene)

“A”: All peptide sequences from this orthologous group (all peptides per gene)

PhyloPat: Gene neighborhood view

• The ‘Gene neighborhood view’ shows all genes from all species in a certain phylogenetic lineage, and all genes in their proximity on the genome (10 genes to both sides)

• Neighbouring genes are color-coded according to the orthologous groups they belong to

• Gene neighborhood gives information about functional relationships (genes involved in similar processes are often clustered together)

• Can be used to find the ‘true’ ortholog from a set of genes, by using not only phylogenetic information but also genomic context

PhyloPat: Gene neighborhood view

Each cell: - Ensembl Gene ID- PhyloPat ID- HGNC Symbol

ERN1 and ERN2 can bedistinguished by lookingAt gene context

Overview

• PhyloPat• Published in BMC Bioinformatics (2006)• Update submitted to Nucleic Acids Res. Database issue

• BioVenn• Revised version submitted to BMC Genomics

• Orthologous networks & OrthoPath• Manuscript in preparation

• CoPub (Taverna workflows)• Published in Nucleic Acids Res. Web Server issue (2008)

BioVenn

• Web application to see the overlap between different lists of biological identifiers, using area-proportional Venn diagrams

• Support of wide range of IDs, which are recognized and linked to the corresponding database: Affymetrix, COG, Ensembl, EntrezGene, Gene Ontology, InterPro, IPI, KEGG Pathway, KOG, PhyloPat and RefSeq

• Optional mapping of Affymetrix and EntrezGene to Ensembl

• Output in SVG (with drag-and-drop functionality) or PNG

• http://www.cmbi.ru.nl/biovenn/

BioVenn

Embedded / standalone, SVG / PNG ID mapping

Absolute numbers / percentages

BioVenn

• Lists for all 13 sets (X total, X only, XY total overlap, XY only overlap, XYZ overlap, etc.)

• If type of ID (e.g. Affymetrix, Ensembl) is recognized, output is linked to the corresponding database

Overview

• PhyloPat• Published in BMC Bioinformatics (2006)• Update submitted to Nucleic Acids Res. Database issue

• BioVenn• Revised version submitted to BMC Genomics

• Orthologous networks & OrthoPath• Manuscript in preparation

• CoPub (Taverna workflows)• Published in Nucleic Acids Res. Web Server issue (2008)

Assessing orthologous biology in groups of genes: Application to GC induced insulin resistance

Biorange meeting 2008-03-11:

Goal: Gain better insight into the conservation of genesinvolved in glucocorticoid induced insulin resistance(GC induced IR) between human, mouse and rat.

Use CoPub to build literature networks, map orthology

Validation needed

Network

Cytochrome P450s

Lipid transport

Adipocyte differentiation

Jak/Stat/IL6Insulin signaling

Fatty acid oxidation/catabolism

Misc: amino acid metabolism, MAPK signaling, osteoblast

Dexamethosone& insulin

Validation approach

Get all genes from a KEGG pathway

Select random 10% of these genes

Create Gene Network using these genes (CoPub)

Compare with original KEGG pathway

Repeat with varying thresholds

Results

Pathway ID # genes in pathway

FP_rate TP_rate Pos.Pred.Val Percentage Manual Pos

Hematopoietic cell lineage hsa04640 88 0.04 0.69 0.11 0.53

Jak-STAT signaling pathway hsa04630 153 0.02 0.54 0.20 0.33

Cytokine-cytokine receptor interaction hsa04060 256 0.03 0.51 0.24 0.53

Toll-like receptor signaling pathway hsa04620 90 0.02 0.50 0.17 0.40

Metabolism of xenobiotics by cytochrome P450 hsa00980 70 0.00 0.50 0.43 0.32

Melanoma hsa05218 71 0.02 0.49 0.11 0.20

Renal cell carcinoma hsa05211 69 0.04 0.49 0.06 0.40

VEGF signaling pathway hsa04370 70 0.04 0.49 0.06 0.20

GnRH signaling pathway hsa04912 97 0.03 0.48 0.09 0.13

Endometrial cancer hsa05213 52 0.02 0.48 0.07 0.47

Average TP = 0.24Average FP = 0.01

Application to all human genes

Create network for each gene with R scaled =30, literature count = 5

Calculate average conservation for each network based on conservation for all the

genes in the network in 4 species (P.tro.,M.mus.,R.nor.,C.fam.)

Get all genes in 100 least conserved

networks

Get all genes in 100 most conserved

networks

Calculate GO enrichment

Calculate GO enrichment

Compare

211 genes 309 genes

6,181 networks with size>2

Term PValue GO:0051704~multi-organism process 1.23E-07 GO:0006952~defense response 1.48E-07 GO:0009615~response to virus 4.47E-06 GO:0051707~response to other organism 2.65E-05 GO:0007586~digestion 7.07E-05 GO:0050896~response to stimulus 1.04E-04 GO:0009607~response to biotic stimulus 4.16E-04 GO:0006955~immune response 6.66E-04 GO:0030101~natural killer cell activation 0.003385226 GO:0007565~female pregnancy 0.003668999

Term PValue GO:0048856~anatomical structure development 5.80E-05 GO:0007399~nervous system development 7.35E-05 GO:0005977~glycogen metabolic process 9.18E-05 GO:0006073~glucan metabolic process 1.02E-04 GO:0048731~system development 1.12E-04 GO:0032502~developmental process 1.16E-04 GO:0007275~multicellular organismal development 2.67E-04 GO:0044262~cellular carbohydrate metabolic process 2.90E-04 GO:0032501~multicellular organismal process 4.49E-04 GO:0006813~potassium ion transport 5.58E-04 GO:0048513~organ development 6.85E-04 GO:0044264~cellular polysaccharide metabolic process 7.09E-04 GO:0005976~polysaccharide metabolic process 7.94E-04

Non-conserved

Conserved

OrthoPath

• OrthoPath is a gene centric search tool for literature networks and their orthologs

• Three input methods:• Single gene search: Get the literature network for a given gene.

OrthoPath will create a network of genes that are connected to this single gene.

• Keyword Search:Get the literature network based on a certain keyword. OrthoPath looks for genes that are connected to the keyword, and creates a network from all these genes.

• Multi Gene Search:Get the literature network for a set of genes. OrthoPath creates a network from only these genes that are entered by the user.

• http://ws2.grid.sara.nl/cgi-bin/orthopath/op.pl

OrthoPathSearch with a single gene

Search with a keyword

Search with a list of genes

Output in HTML, SVG, Cytoscape or Ingenuity format

Set the minimum strength of aco-citation between two keywords

Set the minimum number of abstractsin which a co-citation between the 2genes is found

OrthoPath

Each node in the network:

- EntrezGene information: ID, symbol, description

- number of neighbours

- number of orthologs from human (for all five species)

Overview

• PhyloPat• Published in BMC Bioinformatics (2006)• Update submitted to Nucleic Acids Res. Database issue

• BioVenn• Revised version submitted to BMC Genomics

• Orthologous networks & OrthoPath• Manuscript in preparation

• CoPub (Taverna workflows)• Published in Nucleic Acids Res. Web Server issue (2008)

CoPub Taverna Workflows

• Taverna: free software tool for designing and executing workflows

• Workflow files for CoPub have been

developed:

(1) Search gene

(2) Get literatureneighbours

CoPub Taverna Workflows

(3) Get a list of categories

(4) Get the completenetwork

Acknowledgements

• Wynand Alkema

• Wilco Fleuren

• Raoul Frijters

• Peter Groenen