Biological Expression Language is a knowledge representation language for qualitative causal biology.

1. Natalie Catlett
May 10, 2013
Language Overview
1

2. Contents
• Language Overview
– Statements
– Annotations
– Terms
– Functions
– Relationships
• Knowledge Representation Examples

3. Language Overview
3

4. Language Overview
• BEL statements capture knowledge
• BEL annotations provide information about
statements
– Citation, experimental context, etc.
• BEL terms are composed using BEL functions applied
to namespace values
• BEL relationships connect BEL terms
4

5. BEL Statements
• Basic statement types:
• Complex statement type:
– A causal statement can be used as the target term of a causal statement
5
Term Expression Relationship Term Expression
Term Expression
complex(p(HGNC:CCND1), p(HGNC:CDK4))
p(HGNC:CCND1) directlyIncreases kin(p(HGNC:CDK4))
Term Expression Causal Relationship Causal Statement
p(HGNC:CLSPN) -> (kin(p(HGNC:ATR)) => p(HGNC:CHEK1, pmod(P)))

6. BEL Annotations
• Annotations provide information about one or more BEL
Statements
6
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")

7. BEL Terms
• BEL terms have the following components:
– Function
• Required
• Can be nested to create complex terms
– Namespace Abbreviation
• Optional
– Value
• Required
• If a namespace is given, the value is found in that namespace
• BEL terms from different namespaces are unified during
compilation using information in the BEL Namespace
Equivalence documents
7
f (ns:value)

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

9. BEL Functions
• BEL Functions enable
representation of
different aspects of a
value
– E.g., AKT1 (EGID:207)
can be represented as a
• Gene
• RNA
• Protein
• Modified Protein
• Activity
9

10. Abundance Functions
10
• Most abundance functions take namespace values
– complexAbundance() can take a namespace value OR a list of
abundance terms
– compositeAbundance() must take a list of abundance terms
Short Form Long Form Example Example Description
a() abundance() a(CHEBI:water) the abundance of water
p() proteinAbundance() p(HGNC:IL6) the abundance of human IL6 protein
complex() complexAbundance()
complex(NCH:"AP-1 Complex") the abundance of the AP-1 complex
complex(p(MGI:Fos),
p(MGI:Jun))
the abundance of the complex comprised
of mouse Fos and Jun proteins
composite() compositeAbundance()
composite(p(HGNC:IL6),
a(CHEBI:dexamethasone))
the abundances of IL6 protein and
dexamethasone, together
g() geneAbundance() g(HGNC:ERBB2) the abundance of the ERBB2 gene (DNA)
m() microRNAabundance() m(MGI:Mir21) the abundance of mouse Mir21 microRNA
r() rnaAbundance() r(HGNC:IL6) the abundance of human IL6 RNA

11. Modification Functions
• Modifications are functions used as arguments within
abundance functions
– Post-translational modifications
– Sequence variants (mutations, polymorphisms)
11
Short Form Long Form Example Example Description
pmod() proteinModification()
p(HGNC:AKT1, pmod(P))
the abundance of human AKT1 protein modified
by phosphorylation
p(MGI:Rela, pmod(A, K))
the abundance of mouse Rela protein acetylated
at an unspecified lysine
p(HGNC:HIF1A, pmod(H, N, 803))
the abundance of human HIF1A protein
hydroxylated at asparagine 803
sub() substitution() p(HGNC:PIK3CA, sub(E, 545, K))
the abundance of the human PIK3CA protein in
which glutamic acid 545 has been substituted
with lysine
trunc() truncation() p(HGNC:ABCA1, trunc(1851))
the abundance of human ABCA1 protein that
has been truncated at amino acid residue 1851
via introduction of a stop codon
fus() fusion()
p(HGNC:BCR, fus(HGNC:JAK2, 1875,
2626))
the abundance of a fusion protein of the 5'
partner BCR and 3' partner JAK2, with the
breakpoint for BCR at 1875 and JAK2 at 2626
p(HGNC:BCR, fus(HGNC:JAK2))
the abundance of a fusion protein of the 5'
partner BCR and 3' partner JAK2

12. Process Functions
• Processes include biological phenomena that occur at the
level of the cell or organism
12
Short Form Long Form Example Example Description
bp() biologicalProcess() bp(GO:"cellular senescence")
the biological process cellular
senescence
path() pathology()
path(MESHD:"Pulmonary Disease,
Chronic Obstructive")
the pathology COPD

13. Activity Functions
• Applied to protein and complex abundances to specify the frequency of
events resulting from the molecular activity of the abundance
– This distinction is useful for proteins whose activities are regulated by post-
translational modification
13
Short Form Long Form Example Example Description
cat() catalyticActivity() cat(p(RGD:Sod1)) the catalytic activity of rat Sod1 protein
chap() chaperoneActivity() chap(p(HGNC:CANX))
the events in which the human CANX (Calnexin) protein functions as a
chaperone to aid the folding of other proteins
gtp() gtpBoundActivity() gtp(p(PFH:"RAS Family")) the GTP-bound activity of RAS Family protein
kin() kinaseActivity()
kin(complex(NCH:"AMP-
activated protein kinase
complex"))
the kinase activity of the AMP-activated protein kinase complex
act() molecularActivity() act(p(HGNC:TLR4))
the ligand-bound activity of the human non-catalytic receptor protein
TLR4; a more specific activity function is not applicable to TLR4 protein
pep() peptidaseActivity() pep(p(RGD:Ace)) the peptidase activity of the Rat angiotensin converting enzyme (ACE)
phos() phosphataseActivity() phos(p(HGNC:DUSP1)) the phosphatase activity of human DUSP1 protein
ribo() ribosylationActivity() ribo(p(HGNC:PARP1)) the ribosylation activity of human PARP1 protein
tscript() transcriptionalActivity() tscript(p(MGI:Trp53)) the transcriptional activity of mouse TRP53 (p53) protein
tport() transportActivity()
tport(complex(NCH:"ENaC
Complex"))
the frequency of ion transport events mediated by the epithelial
sodium channel (ENaC) complex

14. Transformation Functions
• Transformations are events in which one class of abundance is
transformed or changed into a second class of abundance
14
Short Form Long Form Example Example Description
deg() degradation() deg(r(HGNC:MYC)) the degradation of human MYC RNA
sec() cellSecretion() sec(p(MGI:Il6)) the secretion of mouse Il6 protein
surf() cellSurfaceExpression() surf(p(RGD:Fas))
the translocation of Rat Fas protein to
the cell surface
tloc() translocation()
tloc(p(HGNC:NFE2L2), MESHCL:Cytoplasm,
MESHCL:"Cell Nucleus")
the event in which human NFE2L2
protein is translocated from the
cytoplasm to the nucleus
rxn() reaction()
rxn(reactants(a(CHEBI:phophoenolpyruvate),
a(CHEBI:ADP)),products(a(CHEBI:pyruvate),
a(CHEBI:ATP)))
the event in which the reactants
phosphoenolpyruvate and ADP are
converted into the products pyruvate
and ATP

15. BEL Relationships
• Causal relationships
– increases, directlyIncreases, decreases, directlyDecreases, rateLimiting
StepOf, 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
15

16. Knowledge Representation Examples
16

17. Knowledge Capture – Example 1
• From published paper describing effects of Tnf in rat
chondrocytes
17

18. Knowledge Capture – Example 1
18
SET Citation = {"PubMed","Arthritis Res Ther.","19144181"}
SET Species = "10116"
SET Cell = "Chondrocytes"
SET Evidence = "we identified the relative changes in
transcript levels of the extracellular matrix components
Agc1, Hapln1, and Col2a1, proteases Mmp-9 and Mmp-12, as
well as the inflammatory cytokine macrophage Csf-1 (Figure
3). TNFα decreased Agc1 and Hapln1 (Figure 3a, b) and
increased Mmp-9 and Mmp-12 (Figure 3e, f)"
p(RGD:Tnf) -> r(RGD:Mmp9)
p(RGD:Tnf) -> r(RGD:Mmp12)
p(RGD:Tnf) -| r(RGD:Acan) // Agc1 = Acan
p(RGD:Tnf) -| r(RGD:Hapln1)
Perturbation (source term)
= Tnf protein
Measurements (target
terms) = RNA abundance
In-line
comment
Experimental context = Rat
chondrocytes
Text from
paper
supporting
statements
Reference

19. Knowledge Capture – Example 2
19
SET Citation = {"PubMed", "Anticancer Agents Med
Chem. 2010 Oct 1;10(8):617-24.","21182469"}
SET Evidence = "One non-synonymous SNP 538G>A
(Gly180Arg) has been found to greatly
affect the function and stability of de novo
synthesized ABCC11 (Arg180) variant
protein. The SNP variant lacking N-linked
glycosylation is recognized as a misfolded
protein in the endoplasmic reticulum (ER) and readily
undergoes proteasomal
degradation. "
p(HGNC:ABCC11, sub(G,180,R)) =|
p(HGNC:ABCC11, pmod(G,N))
p(HGNC:ABCC11, pmod(G,N)) =| deg(p(HGNC:ABCC11))
Gly180Arg variant ABCC11
protein lacks glycosylation
ABCC11 glycosylation
blocks degradation
• Protein variants and post-translational modifications

20. Knowledge Capture – Example 3
• Microarray data – can use probe set ID as identifier
20
SET Citation = {"PubMed","J Exp Med. 2006 Nov
27;203(12):2763-77.","17116732"}
SET Evidence = "Table S1. Affymetrix U133 Plus 2.0
GeneChip array data showing transcripts in HDLECs
up- or down-regulated by a factor of at least
twofold (P < 0.1) after stimulation with TNF-α."
SET Tissue = "Endothelium, Lymphatic"
p(HGNC:TNF) -> r(HGU133P2:205476_at)
p(HGNC:TNF) -> r(HGU133P2:215101_s_at)
p(HGNC:TNF) -> r(HGU133P2:214974_x_at)
p(HGNC:TNF) -> r(HGU133P2:203868_s_at)
p(HGNC:TNF) -| r(HGU133P2:235683_at)
p(HGNC:TNF) -| r(HGU133P2:235150_at)
p(HGNC:TNF) -| r(HGU133P2:205258_at)

21. Knowledge Capture – Example 4
• Protein modifications and activities
21
SET Citation = {"PubMed","Proc Natl Acad Sci U S A 2000 Oct
24 97(22) 11960-5","11035810"}
SET Evidence = "GSK-3 activity is inhibited through
phosphorylation of serine 21 in GSK-3 alpha and serine 9 in
GSK-3 beta."
SET Species = "9606"
p(HGNC:GSK3A,pmod(P,S,21)) =| kin(p(HGNC:GSK3A))
p(HGNC:GSK3B,pmod(P,S,9)) =| kin(p(HGNC:GSK3B))
SET Evidence = "These serine residues of GSK-3 have been
previously identified as targets of protein kinase B
(PKB/Akt)"
kin(p(PFH:"AKT Family")) => p(HGNC:GSK3A,pmod(P,S,21))
kin(p(PFH:"AKT Family")) => p(HGNC:GSK3B,pmod(P,S,9))
New Evidence Line;
Citation and Species
still apply to
statements that
follow