principles for building biomedical ontologies: a go perspective

April 19, 2023

Principles for Building Biomedical Ontologies:

A GO Perspective David Hill

Mouse Genome Informatics

The Jackson Laoratory

April 19, 2023

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

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Tactile senseTactionTactition

?

The Challenge of Univocity:People call the same thing by different names

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Tactile senseTactionTactition

perception of touch ; GO:0050975

Univocity: GO uses 1 term and many characterized synonyms

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= bud initiation

= bud initiation

= bud initiation

The Challenge of Univocity: People use the same words to describe different things

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Bud initiation? How is a computer to know?

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= bud initiation

sensu Metazoa

= bud initiation

sensu Saccharomyces

= bud initiation

sensu Viridiplantae

Univocity: GO adds “sensu” descriptors to discriminate among organisms

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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

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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.

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The Challenge of Positivity: Sometimes absence is a distinction in a Biologist’s mind

non-membrane-bound organelle

GO:0043228 membrane-bound organelle

GO:0043227

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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!

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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 a gene product with

respect to these

We don’t know anything about the ligand that

binds this type of GPCR

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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.

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GPCRs with unknown ligands

We could annotate to

this

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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

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Is_a diamond in GO Process

behavior

locomotory behavior larval behavior

larval locomotory behavior

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Is_a diamond in GO Functionenzyme regulator

activity

GTPase regulatoractivity

enzyme activatoractivity

GTPase activatoracivity

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Is_a diamond in GO Cellular Component

organelle

non-membrane boundorganelle

intracellularorganelle

non-membrane boundintracellular organelle

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Technically the diamonds are correct, but could be eliminated






What do these pairs have in common?

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What do the middle pair of terms all have in common?






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They are all differentiated from the parent term by a different factor






Type of behavior vs. what is behaving

What is regulated vs. type of regulator

Type of organelle vs. location of organelle

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Insert an intermediate grouping term

behavior



behavior of a thing

descriptive behavior

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Why insert terms that no one would use?

behavior

locomotory behavior larval behavior rhythmic behavior adult behavior

By the structure of this graph, locomotory behaviorhas the same relationship to larval behavior

as to rhythmic behavior

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Why insert terms that no one would use?

behavior

locomotory behavior larval behaviorrhythmic behavior adult behavior

But actually, locomotory behavior/rhythmic behaviorand larval behavior/adult behavior group naturally

Descriptivebehavior

Behaviorof athing

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Is_a diamond in GO Process

behavior



The realtionships differentiate behavior in different ways

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GO DefinitionsA definition written by

a biologist:necessary & sufficient

conditions written definition(not computable)

Graph structure: necessary conditions

formal(computable)

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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

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Placement in the graph

Example- Proteasome complex

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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)?

Catalytic activity

protein kinase activity

protein Ser/Thr kinase activity

Cyclin dependent protein kinase activity

Cyclin dependent protein kinase regulator activity

Molecular_function

Enzyme regulator activity

Protein kinase regulator activity

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True path violationWhat is it?

..”the pathway from a child term all the way up to its top-level parent(s) must always be true".

chromosome

Mitochondrial chromosome

Is_a relationship

Part_of relationship

nucleus

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True path violationWhat is it?

..”the pathway from a child term all the way up to its top-level parent(s) must always be true".

nucleus chromosome

Nuclear chromosome

Mitochondrial chromosome

Is_a relationshipsPart_of relationship

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GO textual definitions: Related GO terms have similarly structured (normalized) definitions

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Structured definitions contain both genus and differentiae

Essence = Genus + Differentiae

neuron cell differentiation =Genus: differentiation (processes whereby a relativelyunspecialized cell acquires the specialized features of..)Differentiae: acquires features of a neuron

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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

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Ontology alignmentOne of the current goals of GO is to align:

cone cell fate commitment retinal_cone_cell

keratinocyte differentiation keratinocyte

adipocyte differentiation fat_cell

dendritic cell activation dendritic_cell

lymphocyte proliferation lymphocyte

T-cell homeostasis T_lymphocyte

garland cell differentiation garland_cell

heterocyst cell differentiation heterocyst

Cell Types in GO Cell Types in the Cell Ontologywith

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Alignment of the Two Ontologies will permit the generation of consistent and complete definitions

id: CL:0000062name: osteoblastdef: "A bone-forming cell which secretes an extracellular matrix. Hydroxyapatite crystals are then deposited into the matrix to form bone." [MESH:A.11.329.629]is_a: CL:0000055relationship: develops_from CL:0000008relationship: develops_from CL:0000375

GO

Cell type

New Definition

+

=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.

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Alignment of the Two Ontologies will permit the generation of consistent

and complete definitions

id: GO:0001649

name: osteoblast differentiationsynonym: osteoblast cell differentiationgenus: differentiation GO:0030154 (differentiation)differentium: acquires_features_of CL:0000062 (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

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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

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But Eventually…

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But, what about instances?

What are the instances we are dealing with in our work as ontology builders

and scientific curators?

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What knowledge are we trying to capture?

We are interested in understanding how genes contribute to the biology of

an organism.

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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

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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”.

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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

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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

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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

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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. 2001 Nov 23;276(47):44083-90.

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The Annotation:

The Observation

NAD+

NADHH+

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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.

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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. 1997 Sep 15;100(6):1590-5.

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The Annotation:

The Observation

X X

IMP

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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

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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 RLMice lacking both subunits of lysosomal beta-hexosaminidase display gangliosidosis and mucopolysaccharidosis.Nat Genet 1996 Nov;14(3):348

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The Annotation:

The Observation

X

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The Annotation:

The Observation

IGI

X

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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

April 19, 2023

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):7090-9.

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The Annotation:

The Observation

IPI

NDN

NDN

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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

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What About Biological Process?

It is very similar to function with a few exceptions

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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):357-72.

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The Annotation:

The Observation

IMP

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The Annotation:

The Observation

IMP

X

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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 occursit is the result of moleculesof a gene product executing

their molecular function

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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 conclusionsabout gene product typesbased on the accumulated

experimental data!

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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

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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

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If we comprehensively annotate genes, can we make

the same conclusions?

This is the basis of biological discovery!

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A tribute to Lewis CarrollOnce 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 despisedCan a baby can manage a crocodileNo!

principles for building biomedical ontologies: a go perspective

Documents

membrane bound organelle

membranebound organellego

membranebound organellethe

nonmembranebound organelle

biologists mindnonmembrane

challenge of objectivity

thesewe dont

knowledgewe dont