the comparative toxicogenomics database: connecting ... · the comparative toxicogenomics database:...

The Comparative Toxicogenomics Database: connecting chemicals, genes, and diseases Allan Peter Davis 1 , Carolyn J. Mattingly 1 , Michael C. Rosenstein 1 , Thomas Wiegers 1 , John N. Forrest, Jr. 1,2 , James L. Boyer 1,2 1 The Mount Desert Island Biological Laboratory, Salisbury Cove, Maine 04672 2 Yale University School of Medicine, New Haven, CT 06520 Leveraging Curated Interactions in CTD: exploring integrated data from the perspective of a Gene, Chemical, or Disease 5 Distribution/ Metabolism Cell Death/ Differentiation DNA Repair Cell Cycle Control GENES CHEMICAL DISEASE Phenotype Most chronic diseases involve interactions between environmental factors and genes that modulate physiological processes. Understanding chemical–gene interactions will help resolve: disease predisposition therapeutic drug interactions health risks differential susceptibility to chemical exposures We have taken a bioinformatics approach and are developing the Comparative Toxicogenomics Database (CTD) as a way to explore chemical-gene interactions in different organisms. Dispersed data is integrated and curated to produce a unique database for the cross-species analysis of chemical, gene/protein, and disease relationships. Manual curation of text-mined literature captures details for every chemical-gene interaction via controlled vocabularies. Sequences GenBank UniProt 1.2 million Chemicals MeSH 59,000 References PubMed 78,000 Diseases OMIM 6,000 Discover information http://ctd.mdibl.org/ CTD Mus musculus Arsenic trioxide results in increased phosphorylation of Akt1 protein PMID: 15688020 CV: organism CV: chemical CV: action qualifier CV: action term CV: gene qualifier CV: gene wicked cool Text mining = FAST Manual curation = ACCURATE Chemicals, Genes, & Diseases The CTD Bioinformatics Approach CTD uses both Text Mining + Manual Curation User-Friendly Query Pages 1 2 3 4 Integration of additional data with chemicals and genes in CTD will enable users to evaluate these interactions and form hypotheses about their roles in disease (e.g., can interactions with genes help explain the correlation between LPS and the onset or severity of asthma?). Using CTD to develop hypotheses 6 Using CTD to build Chemical-Gene-Disease networks 7 DISEASE Click to OMIM for disease description Find multiple genes associated with the same disease and chemical. Find GO attributes for genes associated with the same disease or find other diseases caused by the gene. Navigation tabs help optimize the display of information CHEMICAL GENE See top 10 chemical interactions See all interacting chemicals (ranked) Interaction tab shows details of the chemical- gene interaction. Click to PubMed article Export data to desktop 265 genes Q: arsenicals affect expression of which DNA-binding genes? See top 10 gene interactions See all interacting genes (ranked) Begin building putative “chemical-gene-disease” networks Sort data by clicking on any column header CURRENT STATISTICS 29,911 interactions 2,599 chemicals 4,683 genes Testable Hypothesis: 122 potentially novel chemical connections to ABCB11 (and it’s associated disease ) 122 chemicals affect the activity or expression of CYP3A4 CYP3A4 affects the metabolism of at least 5 chemicals which also happen to affect the expression or activity of ABCB11. activity or expression CYP3A 4 122 CYP3A 4 ABCB1 1 Progressive familial intrahepatic cholestasis 2 Pulmonary disease Asthma Psoriasis Hemachromatasis Activity Transport Localization Expression ABCB11 92 curated chemical interactions Phosphorylation LPS LPS Transport Activity Expression Phosphorylation Localization LPS 372 curated gene interactions Q: what interactions describe chemical effects on genes involved in skeletal development? metabolism 5 activity or expression 5 876 interactions

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Page 1: The Comparative Toxicogenomics Database: connecting ... · The Comparative Toxicogenomics Database: connecting chemicals, genes, and diseases Allan Peter Davis1, Carolyn J. Mattingly1,

1The Mount Desert Island Biological Laboratory, Salisbury Cove, Maine 04672 2Yale University School of Medicine, New Haven, CT 06520

Leveraging Curated Interactions in CTD: exploring integrated data from the perspective of a Gene, Chemical, or Disease5

Distribution/Metabolism

Cell Death/Differentiation

DNARepair

Cell CycleControl

GENES

CHEMICAL

DISEASE

Phenotype

Most chronic diseases involve interactions between environmental factors and genes that modulate physiological processes.

Understanding chemical–gene interactions will help resolve: disease predisposition therapeutic drug interactions health risks differential susceptibility to chemical exposures

We have taken a bioinformatics approach and are developing the Comparative Toxicogenomics Database (CTD) as a way to explore chemical-gene interactions in different organisms.

Dispersed data is integrated and curated to produce a unique database for the cross-species analysis of chemical, gene/protein, and disease relationships.

Manual curation of text-mined literature captures details for every chemical-gene interaction via controlled vocabularies.

SequencesGenBankUniProt

1.2 million

ChemicalsMeSH59,000

ReferencesPubMed78,000

DiseasesOMIM6,000

Discoverinformation

http://ctd.mdibl.org/

CTD

Mus musculus

Arsenic trioxide results in increased phosphorylation of Akt1 protein

PMID: 15688020

CV: organism

CV: chemical

CV: action qualifier

CV: action term

CV: gene qualifier

CV: gene

wicked cool

Text mining = FAST

Manual curation = ACCURATE

Chemicals, Genes, & Diseases The CTD Bioinformatics Approach CTD uses both Text Mining + Manual Curation User-Friendly Query Pages1 2 3 4

Integration of additional data with chemicals and genes in CTD will enable users to evaluate these interactions and form hypotheses about their roles in disease (e.g., can interactions with genes help explain the correlation between LPS and the onset or severity of asthma?).

Using CTD to develop hypotheses6

Using CTD to build Chemical-Gene-Disease networks7

DIS

EASE

Click to OMIM fordisease description

Find multiple genes associated with the same disease and chemical.

Find GO attributes for genes associated with the same disease or find other diseases caused by the gene.

Navigation tabs help optimize the display of information

EMIC

GEN

See top 10 chemical interactions

See all interacting chemicals