OpenBEL Initiative BEL-RDF

OpenBEL InitiativeBEL-RDF

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Clinical Semantic Technologies

Objectives

• Create an RDF model that can represent BEL scripts with high (sufficient) accuracy: round-trip conversions

• Define a semantic mapping with as much clarity and fidelity as possible between BEL causal scripts and standard RDF semantics– Entities, Abundances, Processes, Modifiers, Citations , Metadata

• Apply various Semantic tools (SPARQL) to BEL RDF and see what is possible



Some Bio Basics…

• Gene expression -> protein synthesis



Some Bio Basics…

• And then proteins get modified…



Some Bio Basics…

• Everything works together in…



Relevance to Drug R&D

• The current model of applying chemistry and biology (reductionist assays) is not working for Pharmaceuticals companies

• Drug researchers need to understand biology more completely – genomics, protein interactions, systems, cells…

• That means understanding “cause and effect”!



Selventa’s OpenBEL

• OpenBEL is about representing molecular and processes as cause-and-effect…

proteinAbundance(MGI:Jak1,proteinModification(P)) directlyIncreases kinaseActivity(proteinAbundance(MGI:Jak1))

proteinAbundance(MGI:Il13) increases proteinAbundance(MGI:Pik3r1,proteinModification(P))

proteinAbundance(MGI:Il13) increases proteinAbundance(MGI:Ptpn11,proteinModification(P))proteinAbundance(MGI:Il4) increases proteinAbundance(MGI:Nr0b2,proteinModification(P))proteinAbundance(MGI:Inpp5d) decreases transcriptionalActivity(proteinAbundance(MGI:Stat3))proteinAbundance(MGI:Pias3) decreases transcriptionalActivity(proteinAbundance(MGI:Stat3))complexAbundance(proteinAbundance(MGI:Stat3),proteinAbundance(MGI:Stat3)) directlyIncreases transcriptionalActivity(proteinAbundance(MGI:Stat3))

proteinAbundance(HGNC:IL4) increases proteinAbundance(HGNC:IRS2,proteinModification(P,Y))

…



BEL Semantics

• IFNA1 -> CISH transcription p(HGNC:IFNA1) r(HGNC:CISH) :IFNA1-prot-abundance :increase_indirecteffects :CISH-mRNA-

abundance .

• IL2 Modifications p(HGNC:IL2, pmod(P, S, 21), trunc(33)) => r(HGNC:CISH) :IL2-prot-abundance :has_modification pmod(P, S, 21) ,

trunc(33)) ;:increase_directeffects :CISH-mRNA-abundance .



Insights into BEL

• Abundances and Activities (of genes, proteins, RNA, Cmpds) are the primary actors in BEL

• Abundances of some proteins can have associated Activities• Proteins can have Modifications, therefore their Modified

forms also have Abundances • Abundances or Activities can influence other Abundances or

Activities through Effects• Effects can be either increasing or decreasing, and either

direct or indirect



RDF Semantic Mappings

Some conscious decisions:• Abundances and Activities are distinct from

Genes and Proteins, but associated to them as classes

• Abundances and Activities can have Modifications (e.g., protein)

• Effects can be modeled as Binary Operations• Effects can cause other Effects: Series and

Cascades



Abundances/Activities Semantics

Why are Abundances different from Molecules?• Molecules are structural entities, but in order to have

physiological and biochemical effects in a particular context, additional concepts need to be included:– abundance/quantitation (Q)– activity/activation (A)

• These introduce additional dimensions of quantity en mass within a locality, context, state, and dynamics

• Modifications requires their own Abundances



Simple Example

BELp(HGNC:IFNA1) -> r(HGNC:CISH) // protein abundance of IFNA1 increases the mRNA of CISH

RDFns1:IFNA1_proteinAbundance a bel:ProteinAQC ;

bel:affects ns1:IFNA1_CISH_IndirectIncreaseEffect_1 ;bel:has_child HGNC:IFNA1 ;bel:child_for_protein_abundance HGNC:IFNA1 .

ns1:CISH_rnaAbundance a bel:MrnaAQC ;bel:is_affected_by ns1:IFNA1_CISH_IndirectIncreaseEffect_1 ;bel:has_child HGNC:CISH ;bel:child_for_mrna_abundance HGNC:CISH .

ns1:IFNA1_CISH_IndirectIncreaseEffect_1 a bel:IndirectIncreaseEffect ;bel:rel_affects ns1:CISH_rnaAbundance ;bel:rel_is_affected_by ns1:IFNA1_proteinAbundance .

p(IFNA1)

➜

p(CISH)

IFNA1 CISHmolecule

abundance

Causal effect



A little more complexRegulating regulation

PARP1

XRCC5 ribo mod

DNA-NAD+

XRCC5

NAD+ DNA

PARP1ribo activity

PARP1abundance

↓

⇒++⟸

composite(a(CHEBI:"deoxyribonucleic acid"), a(CHEBI:"NAD(+)")) -> (ribo(p(HGNC:PARP1)) => p(HGNC:PARP1, pmod(R)))composite(a(CHEBI:"deoxyribonucleic acid"), a(CHEBI:"NAD(+)")) -> (ribo(p(HGNC:PARP1)) => p(HGNC:XRCC5, pmod(R)))p(HGNC:XRCC5, pmod(R)) => ribo(p(HGNC:PARP1))

↓Evidence A

PARP1ribo mod

⇒+



SPARQL->Cytoscape



SPARQL->Cytoscape



BEL Ontology

BEL Ontology has three super classes:1. Causal Nodes2. Script (Utility) Nodes3. Molecular (External) Entities



BEL Causal Classes

BEL Causal classes define AQC and AQM classes, which are the Affecters and Effectors.

Relationships connect them causally to each other.

Modifications allow modifier extensions to the AQM classes.



BEL AQM ClassesActivity and Quantitative Molecular Classes

AQM classes include the full range of molecular interaction entities.

Both Quantity and Activity are considered here.



BEL Relationships ClassesCause and Correlation

Relationships have to higher forms:

Causal and Correlation

Causes can be direct or indirect, increase or decrease.

Correlations can be positive or negative.



BEL Modification ClassesState changes

Modifications alter protein structures, yet each change needs to be associated with the abundance and activity of that modification type.



BEL Activities and Processes

Activities are associated with dynamics and activity states.



BEL Utility and External Classes

BEL ScriptNodes support all of the BEL document definitions and metadada.• Citations• Evidence• Context• Annotations• NamespaceComments (can be overridden)



Applications

• Inferring downstream consequences• Finding all upstream antecedents• Indexing all +/- effectors and their dependencies• Identifying regulatory or dependence “hubs” • Comparing different observed contexts for

variations in outcomes• Determining necessary conditions for certain

reactions: missing factors• Hypothesis Formation



Comparisons

• BioPAX – Molecular reactions ontology that currently does not support causal effects (e.g, equilibrium direction?) or bio-context

• SBML – Focus on “assumed” math models; requires detailed information

• OpenBEL RDF includes – Negative (absence of effect) assertions– Cataloging different contexts– Protein modification effects (switches)– New causal rules can be added as BEL statements



Summary

• BEL-RDF is based on the BEL Language• BEL-RDF models effects and relations as nodes• Offers a context/evidence based view of

molecular (causal) mechanisms• Intended to map external molecular and

process URIs• Supports the layering of causal rules

Documents

OpenBEL Initiative BEL-RDF