1. August 2012 This work is licensed under the Creative Commons Attribution 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by/3.0/ or send a letter to Creative Commons, 444 Castro Street, Suite 900, Mountain View, California, 94041, USA. 1 Biological Expression Language Overview

2. Contents BEL Statements BEL Statement Annotations BEL Terms BEL Functions BEL Relationships General Hints

3. BEL Statements Basic statement types: 3 Term ExpressionRelationshipTerm Expression complex(p(HGNC:CCND1), p(HGNC:CDK4)) p(HGNC:CCND1) directlyIncreases kin(p(HGNC:CDK4))

4. BEL Statements 4 a(CHEBI:corticosteroid) -> path(MESHD:"Insulin Resistance") Term ExpressionRelationshipTerm Expression The abundance of molecules designated by the name “corticosteroid” in the CHEBI namespace. The pathology designated by the name “Insulin Resistance” in the MESHD namespace.

5. BEL Statements 5 a(CHEBI:corticosteroid) -> path(MESHD:"Insulin Resistance") Term ExpressionRelationshipTerm Expression increases

6. BEL Statements Complex statement type: – A causal statement can be used as the target term of a causal statement 6 Term ExpressionCausal RelationshipCausal Statement p(HGNC:CLSPN) -> (kin(p(HGNC:ATR)) => p(HGNC:CHEK1, pmod(P)))

7. Contents BEL Statements BEL Statement Annotations BEL Terms BEL Functions BEL Relationships General Hints

8. BEL Statement Annotations Annotations provide information about one or more BEL Statements 8 SET Citation = {"PubMed", "J Mol Med", "12682725", "2003- 03-14","Limbourg FP|Liao JK",""} SET Evidence = "high-dose steroid treatment decreases vascular inflammation and ischemic tissue damage after myocardial infarction and stroke through direct vascular effects involving the nontranscriptional activation of eNOS" SET Species = "9606" SET Tissue = "Vascular System" SET Disease = "Stroke" a(CHEBI:corticosteroid) -| bp(MESHD:"Inflammation")

9. Contents BEL Statements BEL Statement Annotations BEL Terms BEL Functions BEL Relationships General Hints

10. BEL Terms BEL terms minimally have the following components: – Function Required Can be nested to create complex terms – Namespace Abbreviation Optional – Value Required Generally found in the referenced namespace BEL terms using values from different namespaces can be equivalenced 10 function(ns:value)

11. BEL Terms 11 a(CHEBI:corticosteroid) function - abundance() function - pathology() path(MESHD:"Insulin Resistance")

12. BEL Terms 12 a(CHEBI:corticosteroid) Namespace abbreviation - CHEBI Namespace abbreviation – MESHD path(MESHD:"Insulin Resistance")

13. BEL Terms 13 a(CHEBI:corticosteroid) Namespace value bp(MESHD:"Insulin Resistance")

14. Equivalence of Terms p(EG:207) p(SPAC:P31749) p(HGNC:AKT1) “the abundance of the protein designated by EntrezGene id 207” (human AKT1) “the abundance of the protein designated by Swiss-Prot id P31749” (human AKT1) “the abundance of the protein designated by HGNC gene symbol ‘AKT1’” (human AKT1) Terms are unified during compilation using information in the BEL namespace equivalence documents Can unify to p(HGNC:AKT1) in the KAM

15. Contents BEL Statements BEL Statement Annotations BEL Terms BEL Functions BEL Relationships General Hints

16. BEL Functions Types of functions: – Abundances – Processes – Modifications of abundances – Activities – Transformations – List functions Abundances and processes are applied directly to namespace values All other functions are applied to abundance functions!

17. BEL Functions - Abundances Abundances – abundance(), a() – geneAbundance(), g() – rnaAbundance(), r() – microRNAAbundance(), m() – complexAbundance(), complex() – compositeAbundance(), composite() 17

18. abundance(), a() Use abundance() to represent any abundances that are not represented by a more specific abundance type, including: – Chemicals a(CHEBI:corticosteroid) – Cellular structures a(GOCCTERM:"astral microtubule") No modification functions apply to abundance terms Generally, activity functions do not apply to abundance terms 18

19. geneAbundance(), g() Use geneAbundance terms to represent DNA – Can use to represent gene amplification and deletion events – Used in "gene scaffolding" g(HGNC:AKT1) transcribedTo r(HGNC:AKT1) – Use in complexes to represent binding to promoters complex(p(HGNC:TP53), g(HGNC:CDKN1A)) In BEL v1.0, the only modification function that can be applied to gene abundances is fusion() – g(HGNC:TMPRSS2,fusion(HGNC:ERG)) No activity functions apply to geneAbundance terms 19

20. complexAbundance(), complex() Use complexAbundance() to represent molecular complexes and binding events complexAbundance terms can take two forms: – complexAbundance(ns:value) Used for named complexes E.g., complexAbundance(NCH:"AP-1 Complex") – complexAbundance( ) Use to represent binding events or to define complexes by components Unordered list E.g., complex(p(HGNC:FOS),p(HGNC:JUN)) 20

21. compositeAbundance(), composite() Use to represent cases where multiple abundances synergize to produce an effect – Composite terms should not be used if any of the abundances alone are reported to cause the effect – Use composite terms only as subjects of statements – E.g., composite(p(HGNC:TGFB1), p(HGNC:IL6)) 21

22. BEL Functions - Processes Processes include biological phenomena that occur at the level of the cell or organism – biologicalProcess(), bp() E.g., bp(GO:"cellular senescence") – pathology(), path() E.g., path(MESHD:"Muscle Hypotonia") 22

23. BEL Functions – Abundance Modifications Modifications are functions used as arguments within abundance functions Currently supported modification types are: – Variants - use to represent protein sequence variants, generally resulting from a mutation or polymorphism substitution(), truncation(), fusion() E.g., p(HGNC:PIK3CA, sub(E, 545, K)) – PIK3CA protein with glutamic acid 545 substituted with a lysine – Protein Modifications - use to represent post-translational modifications of proteins Includes phosphorylation, ubiquitination, acetylation, glycosylation proteinModification() E.g., p(HGNC:HIF1A, pmod(H, N, 803)) – Modification of HIF1A by hydroxylation at amino acid asparagine 803 23

24. BEL Functions - Activities Activity functions are applied to protein, complex, and RNA abundances to specify the frequency of events resulting from the molecular activity of the abundance – E.g., tport(complex(NCH:"EnaC Complex")) Transporter activity of the EnaC sodium channel complex This distinction is particularly useful for proteins whose activities are regulated by post-translational modification BEL v1.0 supports 10 distinct activity functions: – catalyticActivity, peptidaseActivity, gtpBoundActivity, transportActivity, chaperoneActivity, transcriptionalActivity, molecularActivity, kinaseActivity, phosphataseActivity, ribosylaseActivity molecularActivity() should be used to represent activities that are not represented by a more specific function 24

25. BEL Functions - Transformations Transformations are events in which one class of abundance is transformed or changed into a second class of abundance – Translocations translocation(), tloc() cellSecretion(), sec() cellSurfaceExpression(), surf() – Reactions reaction(), rxn() – Degradation degradation(), deg() 25

26. translocation(), tloc() Use translocation terms to represent the movement of abundances from one cellular location to another E.g., tport(complex(NCH:"EnaC Complex")) => \ tloc(a(CHEBI:"sodium(1+)"), MESHCL:"Extracellular Space", \ MESHCL:"Intracellular Space") – The transport activity of the EnaC Complex translocates sodium ions from extracellular to intracellular 26

27. cellSecretion(), sec() cellSurfaceExpression(), surf() sec() and surf() are convenience functions for commonly used translocations 27

28. degradation(), deg() Generally used to indicate complete proteolysis of a protein Do not use to indicate proteolysis which results in functional cleavage products! During compilation Phase I, degradation nodes are linked to the root abundance with a directlyDecreases relationship – E.g., deg(p(HGNC(MAPT)) – Compilation adds: deg(p(HGNC:MAPT)) =| p(HGNC:MAPT)

29. BEL Functions – List Functions List functions used for: – Protein family assignment p(PFH:"Cu-Zn SOD Family") hasMembers list(p(HGNC:SOD1), p(HGNC:SOD3)) – Complex component assignment complex(GOCCTERM:"gamma-secretase complex") hasComponents \ list(p(HGNC:PSEN1),p(HGNC:NCSTN),p(HGNC:APH1A),p(HGNC:PSEN2)) – Reactants and Products within a reaction term rxn(reactants(a(CHEBI:superoxide)), \ products(a(CHEBI:"hydrogen peroxide"))) 29

30. Contents BEL Statements BEL Statement Annotations BEL Terms BEL Functions BEL Relationships General Hints

31. BEL Relationships Causal relationships – increases, directlyIncreases, decreases, directlyDecreases, rateLimitingStepOf, causesNoChange Correlative relationships – negativeCorrelation, positiveCorrelation, association Biomarker relationships – biomarkerFor, prognosticBiomarkerFor Assignment to groups – hasMember, hasComponent, hasMembers, hasComponents Other – isA, subProcessOf Genomic relationships – transcribedTo, translatedTo, orthologousTo 31

32. BEL Relationships – Compiler Inserted Relationships These relationships are not needed for creating BEL statements – Used only by the compiler actsIn hasModification hasProduct hasVariant reactantIn translocates includes 32

33. Contents BEL Statements BEL Statement Annotations BEL Terms BEL Functions BEL Relationships General Hints

34. General BEL Hints BEL functions, relationships, and namespace values are all case sensitive Every term must have a function – Namespace values are always associated with an abundance or process function – Exception - cellular location values within a translocation function Namespace values with spaces or unusual characters require quotes – E.g., complex(GOCCTERM:"gamma-secretase complex") 34