go ontology design dhill

Principles for Building Biomedical Ontologies:A GO Perspective : 

Principles for Building Biomedical Ontologies: A GO Perspective David Hill Mouse Genome Informatics The Jackson Laoratory

How has GO dealt with some specific aspects of ontology development?: 

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

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

Tactile sense Taction Tactition ? The Challenge of Univocity: People call the same thing by different names

Univocity: GO uses 1 term and many characterized synonyms: 

Tactile sense Taction Tactition perception of touch ; GO:0050975 Univocity: GO uses 1 term and many characterized synonyms

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

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

Slide6: 

Bud initiation? How is a computer to know?

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

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

The Importance of synonyms for utility:How do we represent the function of tRNA?: 

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

The Challenge of Positivity: 

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.

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

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

Positivity: 

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!

The Challenge of Objectivity: Database users want to know if we don’t know anything (Exhaustiveness with respect to knowledge): 

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

Objectivity: 

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.

GPCRs with unknown ligands: 

GPCRs with unknown ligands We could annotate to this

Single Inheritance: 

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

Is_a diamond in GO Process: 

Is_a diamond in GO Process behavior locomotory behavior larval behavior larval locomotory behavior

Is_a diamond in GO Function: 

Is_a diamond in GO Function enzyme regulator activity GTPase regulator activity enzyme activator activity GTPase activator acivity

Is_a diamond in GO Cellular Component: 

Is_a diamond in GO Cellular Component organelle non-membrane bound organelle intracellular organelle non-membrane bound intracellular organelle

Technically the diamonds are correct, but could be eliminated: 

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?

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

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

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

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

Insert an intermediate grouping term: 

Insert an intermediate grouping term behavior locomotory behavior larval behavior larval locomotory behavior behavior of a thing descriptive behavior

Why insert terms that no one would use?: 

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

Why insert terms that no one would use?: 

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

Is_a diamond in GO Process: 

Is_a diamond in GO Process behavior locomotory behavior larval behavior larval locomotory behavior The realtionships differentiate behavior in different ways

GO Definitions: 

GO Definitions A definition written by a biologist: necessary & sufficient conditions written definition (not computable) Graph structure: necessary conditions formal (computable)

Relationships and definitions: 

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

Placement in the graph: 

Placement in the graph Example- Proteasome complex

The importance of relationships: 

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

True path violationWhat is it?: 

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". chromosome Mitochondrial chromosome Is_a relationship Part_of relationship nucleus

True path violationWhat is it?: 

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 Nuclear chromosome Mitochondrial chromosome Is_a relationships Part_of relationship

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

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

Structured definitions contain both genus and differentiae: 

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

Basis in Reality: 

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

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

Ontology alignment One 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 Ontology with

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

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

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

Alignment of the Two Ontologies will permit the generation of consistent and complete definitions id: GO:0001649 name: osteoblast differentiation synonym: osteoblast cell differentiation genus: 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

Other Ontologies that can be aligned with GO: 

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

But Eventually…: 

But Eventually…

But, what about instances?: 

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

What knowledge are we trying to capture?: 

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

What do we mean by gene product?: 

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

How do wet-bench biologists learn about gene products?: 

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”.

How do we represent the accumulated knowledge: 

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

So, where are the instances?: 

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

Examples of how we connect instances with knowledge representation in the GO: 

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

Example #1:Molecular Function using IDA: 

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.

The Annotation:: 

The Annotation: The Observation NAD+

What are the instances in this experiment?: 

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.

Example #2:Molecular Function using IMP: 

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.

The Annotation:: 

The Annotation: The Observation X X IMP

What are the instances in this experiment?: 

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

Example #3:Molecular Function using IGI: 

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

The Annotation:: 

The Annotation: The Observation X

The Annotation:: 

The Annotation: The Observation X

The Annotation:: 

The Annotation: The Observation X

The Annotation:: 

The Annotation: The Observation X

The Annotation:: 

The Annotation: The Observation IGI X

What are the instances in this experiment?: 

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

Example #4:Molecular Function using IPI: 

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.

The Annotation:: 

The Annotation: The Observation IPI

The Annotation:: 

The Annotation: The Observation IPI

What are the instances in this experiment?: 

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

What About Biological Process?: 

What About Biological Process? It is very similar to function with a few exceptions

Biological Process Using IMP: 

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.

The Annotation:: 

The Annotation: The Observation IMP

The Annotation:: 

The Annotation: The Observation IMP X

What are the instances in this Experiment?: 

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

How do wet-bench biologists learn about gene products?: 

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!

If experiments show:: 

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

A wet-bench biologist would conclude: 

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

If we comprehensively annotate genes, can we make the same conclusions?: 

If we comprehensively annotate genes, can we make the same conclusions? This is the basis of biological discovery!

A tribute to Lewis Carroll: 

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!