1. Principles for Building Biomedical Ontologies: A GO Perspective
David Hill
Mouse Genome Informatics
The Jackson Laoratory
November 22, 2018

2. How has GO dealt with some specific aspects of ontology development?
Univocity
Positivity
Objectivity
Single Inheritance
Definitions
Formal definitions
Written definitions
Basis in Reality
Universals & Instances
Ontology Alignment
November 22, 2018

3. The Challenge of Univocity: People call the same thing by different names
Tactition
Taction
Tactile sense ?
November 22, 2018

4. Univocity: GO uses 1 term and many characterized synonyms
Taction
Tactition
Tactile sense
perception of touch ; GO:
November 22, 2018

5. The Challenge of Univocity: People use the same words to describe different things
= bud initiation
= bud initiation
= bud initiation
November 22, 2018

6. Bud initiation? How is a computer to know?
November 22, 2018

7. Univocity: GO adds “sensu” descriptors to discriminate among organisms
= bud initiation
sensu Metazoa
= bud initiation
sensu Saccharomyces
= bud initiation
sensu Viridiplantae
November 22, 2018

8. Triplet_codon amino acid adaptor activity
The Importance of synonyms for utility: How do we represent the function of tRNA?
Biologically, what does the tRNA do?
Identifies the codon and inserts the amino acid in the growing polypeptide
Molecular_function
Triplet_codon amino acid adaptor activity
GO Definition: Mediates the insertion of an amino acid at the correct
point in the sequence of a nascent polypeptide chain during protein synthesis.
Synonym: tRNA
November 22, 2018

9. The Challenge of Positivity
Some organelles are membrane-bound.
A centrosome is not a membrane bound organelle,
but it still may be considered an organelle.
November 22, 2018

10. membrane-bound organelle
The Challenge of Positivity: Sometimes absence is a distinction in a Biologist’s mind
non-membrane-bound organelle
GO:
membrane-bound organelle
GO:
November 22, 2018

11. Positivity Note the logical difference between
“non-membrane-bound organelle” and
“not a membrane-bound organelle”
The latter includes everything that is not a membrane bound organelle!
November 22, 2018

12. about a gene product with
The Challenge of Objectivity: Database users want to know if we don’t know anything (Exhaustiveness with respect to knowledge)
We don’t know anything
about the ligand that
binds this type of GPCR
We don’t know anything
about a gene product with
respect to these
November 22, 2018

13. Objectivity
How can we use GO to annotate gene products when we know that we don’t have any information about them?
Currently GO has terms in each ontology to describe unknown
An alternative might be to annotate genes to root nodes and use an evidence code to describe that we have no data.
Similar strategies could be used for things like receptors where the ligand is unknown.
November 22, 2018

14. GPCRs with unknown ligands
We could annotate to this
November 22, 2018

15. Single Inheritance GO has a lot of is_a diamonds
Some are due to incompleteness of the graph
Some are due to a mixture of dissimilar classes within the graph at the same level
November 22, 2018

16. Is_a diamond in GO Process
behavior
locomotory behavior
larval behavior
larval locomotory behavior
November 22, 2018

17. Is_a diamond in GO Function
enzyme regulator
activity
enzyme activator
activity
GTPase regulator
activity
GTPase activator
acivity
November 22, 2018

18. Is_a diamond in GO Cellular Component
organelle
intracellular
organelle
non-membrane bound
organelle
non-membrane bound
intracellular organelle
November 22, 2018

19. Technically the diamonds are correct, but could be eliminated
locomotory behavior
larval behavior
GTPase regulator
activity
enzyme activator
activity
non-membrane bound
organelle
intracellular
organelle
What do these pairs have in common?
November 22, 2018

20. What do the middle pair of terms all have in common?
locomotory behavior
larval behavior
GTPase regulator
activity
enzyme activator
activity
non-membrane bound
organelle
intracellular
organelle
November 22, 2018

21. They are all differentiated from the parent term by a different factor
locomotory behavior
larval behavior
Type of behavior vs. what is behaving
GTPase regulator
activity
enzyme activator
activity
What is regulated vs. type of regulator
non-membrane bound
organelle
intracellular
organelle
Type of organelle vs. location of organelle
November 22, 2018

22. Insert an intermediate grouping term
behavior
behavior of
a thing
descriptive
behavior
locomotory behavior
larval behavior
larval locomotory behavior
November 22, 2018

23. Why insert terms that no one would use?
behavior
larval behavior
rhythmic behavior
adult behavior
locomotory behavior
By the structure of this graph, locomotory behavior
has the same relationship to larval behavior
as to rhythmic behavior
November 22, 2018

24. Why insert terms that no one would use?
behavior
Behavior
of a
thing
Descriptive
behavior
rhythmic behavior
larval behavior
adult behavior
locomotory behavior
But actually, locomotory behavior/rhythmic behavior
and larval behavior/adult behavior group naturally
November 22, 2018

25. Is_a diamond in GO Process
behavior
locomotory behavior
larval behavior
larval locomotory behavior
The realtionships differentiate
behavior in different ways
November 22, 2018

26. GO Definitions A definition written by a biologist:
necessary & sufficient
conditions
written definition
(not computable)
Graph structure: necessary conditions
formal
(computable)
November 22, 2018

27. Relationships and definitions
The set of necessary conditions is determined by the graph
This can be considered a partial definition
Important considerations:
Placement in the graph- selecting parents
Appropriate relationships to different parents
True path violation
November 22, 2018

28. Placement in the graph Example- Proteasome complex November 22, 2018
Mulitple parents for one term; different relationships with different parents.
Example- Proteasome complex
November 22, 2018

29. The importance of relationships
Cyclin dependent protein kinase
Complex has a catalytic and a regulatory subunit
How do we represent these activities (function) in the ontology?
Do we need a new relationship type (regulates)?
Molecular_function
Catalytic activity
Enzyme regulator activity
protein kinase activity
Protein kinase regulator activity
protein Ser/Thr kinase activity
Cyclin dependent protein kinase activity
Cyclin dependent protein kinase regulator activity
November 22, 2018

30. True path violation What is it?
..”the pathway from a child term all the way up to its top-level parent(s) must always be true".
nucleus
Part_of relationship
chromosome
Is_a relationship
Mitochondrial chromosome
November 22, 2018

31. True path violation What is it?
..”the pathway from a child term all the way up to its top-level parent(s) must always be true".
nucleus
chromosome
Part_of relationship
Is_a relationships
Nuclear chromosome
Mitochondrial chromosome
November 22, 2018

32. GO textual definitions: Related GO terms have similarly structured (normalized) definitions
November 22, 2018

33. Structured definitions contain both genus and differentiae
Essence = Genus + Differentiae
neuron cell differentiation =
Genus: differentiation (processes whereby a relatively
unspecialized cell acquires the specialized features of..)
Differentiae: acquires features of a neuron
November 22, 2018

34. Basis in Reality GO is designed by a consortium
As long as egos don’t get in the way, GO represents universals rather than concepts
Large-scale developments of the GO are a result of compromise
Gene Annotators have a large say in GO content
Annotators are experts in their fields
Annotators constantly read the scientific literature
November 22, 2018

35. Ontology alignment One of the current goals of GO is to align:
Cell Types in GO
Cell Types in the Cell Ontology
with
cone cell fate commitment
retinal_cone_cell
keratinocyte differentiation
keratinocyte
adipocyte differentiation
fat_cell
dendritic cell activation
dendritic_cell
(as of 4/20/05 this was the status)
lymphocyte proliferation
lymphocyte
T-cell homeostasis
T_lymphocyte
garland cell differentiation
garland_cell
heterocyst cell differentiation
heterocyst
November 22, 2018

36. Alignment of the Two Ontologies will permit the generation of consistent and complete definitionsGO +
id: CL:
name: osteoblast
def: "A bone-forming cell which secretes an extracellular matrix. Hydroxyapatite crystals are then deposited into the matrix to form bone." [MESH:A ]
is_a: CL:
relationship: develops_from CL:
relationship: develops_from CL:
Cell type =
Osteoblast differentiation: Processes whereby an osteoprogenitor cell or a cranial neural crest cell acquires the specialized features of an osteoblast, a bone-forming cell which secretes extracellular matrix.
New Definition
November 22, 2018

37. Alignment of the Two Ontologies will permit the generation of consistent and complete definitions
id: GO:
name: osteoblast differentiation
synonym: osteoblast cell differentiation
genus: differentiation GO: (differentiation)
differentium: acquires_features_of CL: (osteoblast)
definition (text): Processes whereby a relatively unspecialized cell acquires the specialized features of an osteoblast, the mesodermal cell that gives rise to bone
Formal definitions with necessary and sufficient conditions, in both human readable and computer readable forms
November 22, 2018

38. Other Ontologies that can be aligned with GO
Chemical ontologies
3,4-dihydroxy-2-butanone-4-phosphate synthase activity
Anatomy ontologies
metanephros development
GO itself
mitochondrial inner membrane peptidase activity
November 22, 2018

39. But Eventually…
November 22, 2018

40. But, what about instances?
What are the instances we are dealing with in our work as ontology builders and scientific curators?
November 22, 2018

41. What knowledge are we trying to capture?
We are interested in understanding how genes contribute to the biology of an organism.
November 22, 2018

42. What do we mean by gene product?
Gene Product Type
An abstract representation of a gene
These are the representations we have in MODs
Gene Product Instance
A molecule of a gene product
It can be physically isolated
It takes up space
November 22, 2018

43. How do wet-bench biologists learn about gene products?
They do experiments!
Experiments are designed to study the properties of gene product instances.
Experimental biologists take on “The Burden of Proof”.
November 22, 2018

44. How do we represent the accumulated knowledge
We make annotations!
Annotations connect what wet-bench biologists see in the lab with how we represent our understanding of biology
November 22, 2018

45. So, where are the instances?
The instances are in the lab. We use what people report about instances, but we never actually deal with them directly
November 22, 2018

46. Examples of how we connect instances with knowledge representation in the GO
What follows are examples of annotation of the biomedical literature using GO types, gene product types and evidence codes
November 22, 2018

47. Example #1:Molecular Function using IDA
Figure from
Zhang M, Chen W, Smith SM, Napoli JL.
Molecular characterization of a mouse short chain dehydrogenase/reductase active with all-trans-retinol in intact cells, mRDH1.
J Biol Chem Nov 23;276(47):
November 22, 2018

48. The Observation
NADH H+
NAD+
The Annotation:
November 22, 2018

49. What are the instances in this experiment?
Gene product instances
Molecules of retinol dehydrogenase
Molecular function instances
Instances of execution of the molecular function revealed by the assay
Instances of molecular function associated with instances of retinol dehydrogenase. These instances are the potential of a molecule of retinol dehydrogenase to execute the function retinol dehydrogenase activity.
November 22, 2018

50. Example #2:Molecular Function using IMP
Figure from
Schulz S, Lopez MJ, Kuhn M, Garbers DL.
Disruption of the guanylyl cyclase-C gene leads to a paradoxical phenotype of viable but heat-stable enterotoxin-resistant mice.
J Clin Invest Sep 15;100(6):
November 22, 2018

51. The Observation X X
The Annotation:
IMP
November 22, 2018

52. What are the instances in this experiment?
Gene product instances
Molecules of GUCY2C protein
The lack of functional molecules of GUCY2C in mutants
Molecular function instances
The execution of the molecular function, measured by the accumulation of cGMP
The potential of a molecule of GUCY2C to execute the molecular function
Revealed by the correlation between a lack of molecules and a lack of executions of molecular function
November 22, 2018

53. Example #3:Molecular Function using IGI
Figure from
Sango K; McDonald MP; Crawley JN; Mack ML; Tifft CJ; Skop E; Starr CM; Hoffmann A; Sandhoff K; Suzuki K; Proia RL
Mice lacking both subunits of lysosomal beta-hexosaminidase display gangliosidosis and mucopolysaccharidosis.
Nat Genet 1996 Nov;14(3):348
November 22, 2018

54. The Observation X
The Annotation:
November 22, 2018

55. The Observation X
The Annotation:
November 22, 2018

56. The Observation X
The Annotation:
November 22, 2018

57. The Observation X
The Annotation:
November 22, 2018

58. The Observation X
The Annotation:
IGI
November 22, 2018

59. What are the instances in this experiment?
Gene product instances
Molecules of HEXA protein
Molecules of HEXB protein
The lack of functional HEXA/HEXB protein in mutant cells
Molecular function instances
The execution of the molecular function beta-N-acetylhexosaminidase as measured by glycosaminoglycan accumulation
The potential of a molecule of HEXA/HEXB to execute the molecular function beta-N-acetylhexosaminidase
November 22, 2018

60. Example #4:Molecular Function using IPI
Figure from
Kuwako K; Hosokawa A; Nishimura I; Uetsuki T; Yamada M; Nada S; Okada M; Yoshikawa K
Disruption of the paternal necdin gene diminishes TrkA signaling for sensory neuron survival.
J Neurosci 2005 Jul 27;25(30):
November 22, 2018

61. The Observation
NDN
NDN
The Annotation:
IPI
November 22, 2018

62. The Observation
NDN
NDN
The Annotation:
IPI
November 22, 2018

63. What are the instances in this experiment?
Gene product instances
FLAG-tagged molecules of NTRKA
FLAG-tagged molecules of NGFR
Molecules of NDN
Molecular function instances
The execution of the molecular function protein binding between instances of NDN and NTRKA-FLAG
The execution of the molecular function protein binding between instances of NDN and NGFR-FLAG
The potential of a molecule of NDN to execute protein binding to a molecule of NTRKA-FLAG or NGFR-FLAG
The potential of a molecule of NTRKA-FLAG to execute protein binding to a molecule of NDN
The potential of a molecule of NGFR-FLAG to execute protein binding to a molecule of NDN
November 22, 2018

64. What About Biological Process?
It is very similar to function with a few exceptions
November 22, 2018

65. Biological Process Using IMP
Washington Smoak I; Byrd NA; Abu-Issa R; Goddeeris MM; Anderson R; Morris J; Yamamura K; Klingensmith J;
Meyers EN, Sonic hedgehog is required for cardiac outflow tract and neural crest cell development.,
Dev Biol 2005 Jul 15;283(2):
November 22, 2018

66. The Observation
The Annotation:
IMP
November 22, 2018

67. The Observation X
The Annotation:
IMP
November 22, 2018

68. What are the instances in this Experiment?
Gene product instances
Molecules of the Shh gene
Non-functional molecules of the Shh gene
Biological Process instances
The development of a mouse heart
Molecular Function Instances
The excecution of a molecular function by a molecule of the Shh gene
So, when a process occurs
it is the result of molecules
of a gene product executing
their molecular function
November 22, 2018

69. How do wet-bench biologists learn about gene products?
They do experiments!
Experiments are designed to study the properties of gene product instances.
Experimental biologists take on “The Burden of Proof”.
They make conclusions
about gene product types
based on the accumulated
experimental data!
November 22, 2018

70. If experiments show:
All instances of a gene product studied have the potential to execute the function tyrosine kinase
Instances of the same gene product are involved in the biological process limb development
All instances of the same gene product are found in instances of the cytoplasm
November 22, 2018

71. A wet-bench biologist would conclude
The gene product of this gene is a tyrosine kinase that functions in the cytoplasm and the tyrosine kinase function is used in limb development
November 22, 2018

72. This is the basis of biological discovery!
If we comprehensively annotate genes, can we make the same conclusions?
This is the basis of biological discovery!
November 22, 2018

73. A tribute to Lewis Carroll
Once master the machinery of Symbolic Logic, and you have a mental occupation always at hand, of absorbing interest, and one that will be of real use to you in any subject you may take up. It will give you clearness of thought - the ability to see your way through a puzzle - the habit of arranging your ideas in an orderly and get-at-able form - and, more valuable than all, the power to detect fallacies, and to tear to pieces the flimsy illogical arguments, which you will so continually encounter in books, in newspapers, in speeches, and even in sermons, and which so easily delude those who have never taken the trouble to master this fascinating Art. Lewis Carroll (a)  All babies are illogical. (b)  Nobody is despised who can manage a crocodile. (c)  Illogical persons are despised Can a baby can manage a crocodile No!
November 22, 2018