Biological Expression Language Overview

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. 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: Term Expression Relationship Term Expression p(HGNC:CCND1) directlyIncreaseskin(p(HGNC:CDK4)) Term Expression complex(p(HGNC:CCND1), p(HGNC:CDK4))

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

6. BEL Statements • Complex statement type: • A causal statement can be used as the target term of a causal statement Term Expression Causal Relationship Causal 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 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 function(ns:value) • 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

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

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

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

14. Equivalence of Terms “the abundance of the protein designated by EntrezGene id 207” (human AKT1) p(EG:207) p(SPAC:P31749) p(HGNC:AKT1) “the abundance of the protein designated by Swiss-Prot id P31749” (human AKT1) Can unify to p(HGNC:AKT1) in the KAM “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

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()

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

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) transcribedTor(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

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(<abundance term list>) • Use to represent binding events or to define complexes by components • Unordered list • E.g., complex(p(HGNC:FOS),p(HGNC:JUN))

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))

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:"MuscleHypotonia")

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

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

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()

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

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

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") hasMemberslist(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")))

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

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

33. Contents • BEL Statements • BEL Statement Annotations • BEL Terms • BEL Functions • BELRelationships • 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")