ĐĎॹá>ţ˙ żÁţ˙˙˙˝ž˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙˙ěĽÁ` řżÚlbjbjć‡ć‡ .Ş„í„íŃd˙˙˙˙˙˙¤ęęęę‚‚‚–BxBxBxBx\žx”– ˜h>y(fyfyfyfyÝ|Ý|Ý|ˆ—Š—Š—Š—Š—Š—Š—$q™hٛźŽ—‚Ŕ}ť|"Ý|Ŕ}Ŕ}Ž—ęęfyfyU׊ŠŠŠŠŠŔ}Ěęlfy‚fyˆ—ŠŠŔ}ˆ—ŠŠŠŠrԔTV,‚ԕfy2y @á)ˇěăĆBxŒ…H(•ˆ—Ů—0 ˜6•ž•œÔ‰Ś•œԕԕ•œ‚d–$Ý|"˙|ŠŠ}+}•Ý|Ý|Ý|Ž—Ž—zŠÝ|Ý|Ý| ˜Ŕ}Ŕ}Ŕ}Ŕ}––dú9ţ?D8––úţ?–––ęęęęęę˙˙˙˙ Common Anatomy Reference Ontology Workshop September 8-9, 2006 in Seattle Session I: Principles of Ontology Design Barry Smith - What an Ontology is For Goal of CARO is to make anatomies interoperable. Problem is ontologies are incomplete, there is too much data, and there are gaps in the data. Post-hoc mapping between data vs. prospective standards for categorizing data with a plan for improvement. Science starts with a core of validated truths, then resolves inconsistencies. “Trivialities are our friends” How to link gene products and other scientifically validated data to anatomy and disease GO built on methodology of annotations, add new terms as necessary. Use -> improvements -> better annotations; 5 bangs for GO buck: cross-species integration cross-granularity integration links to things of biomedical relevance semantic searchability human curated science base is benchmark for comparison of non-human models of biology OBO 2004 - Initiation of reform efforts linking GO to other OBO ontologies OBO foundry 2006 – 12 candidate OBO-ontologies including CARO Each foundry member has a prefix identifier, a scope, a URL, and custodians. Martin Ringwald: Why is there not a model organism anatomy ontology in the OBO foundry? Answer, none currently or have yet promised to adhere to the guidelines Ontology coverage of continuants and occurrents- anatomy (continuants) is represented in three ontologies at different levels of granularity. Foundry principles: ontology is freely available is in a common language developers will collaborate when domains overlap (like at this CARO meeting) developers will be responsible for maintenance ontology is orthogonal unique IDs versioning definitions domain content is clearly bounded independent users Uses relations in OBO-REL Rule of single inheritance: No diamonds in is_a hierarchy, ok in part_of hierarchy Cornelius- switching anatomy thinking from part_of to a structural is_a Someone questioned, “How can one build an is_a taxonomy when science isn’t yet settled?” (taxonomy of species I presume?) Barry answered, represent what you know and make additional classes when necessary. Ontology, like every other part of science, needs to take the best current scientific understanding currently available and start from there. Certainly this will contain mistakes, but we can be confident that these will gradually be eliminated, and the mistakes will not be a problem provided our ontologies are subject to update in light of scientific advance. Modules of single inheritance can be used together to build multiple inheritance “views” useful for specific application purposes. With regard to staying with single inheritance (diamond control), Barry made the analogy “Sometimes staying sober is harder than getting drunk.” Single inheritance is not yet an obo foundry principle. What single inheritance brings: coherent hierarchies, modularity, statistical representation, jointly exhaustive pairwise disjoint classification, coherent methodology for definitions : Aristotelian definitions – A = a B which… Canonical must come before pathological. Three canonical ontologies – CARO, ontology of functions, and ontology of developmental processes (part of GO?) Suzi- Awareness that GO has different levels of granularities for mol function and biological process. Continuants (endurants) – continuous existence, preserve identity (me) (can be independent or dependent) Occurrents (processes) – have temporal parts, unfold in time (my life) (every occurrent depends on independent continuants as its participants) Dependent entities – qualities, shapes, roles, functions … Independent entities – cells, molecules, portions of tissue Function vs. functioning: function – to pump blood. Function is realized in process of pumping. Functions are not always realized. OBO-REL part_of, has_part -> need to revisit these in light of David’s development issues, asymmetry with part_of and has_part Located_in without being part_of Transformation_of - same instance Derives_from, fusion or fission New relation- develops_from which would be a parent of both? How about capture (absorption) and budding, where one continuant continues to exist in time.? Ex. stem cells. Do we need points as well as temporal periods? Yes. Fiat vs. bona fide boundaries. Varieties of fiat boundaries in anatomical structures, body spaces, temporal. Kinds of connection- attached_to, synapsed_with, continuous_with A is continuous_with B if A shares a fiat boundary with B. Symmetric on instance but not universal level. Do regions have indeterminacy? Body parts vs body regions Body = whole organism or trunk? Count nouns (suitcase), mass nouns (luggage, sugar). Mass nouns are a problem, use “portion of” Chris Mungall - Application of OBO Foundry Principles in GO GO is 3 orthogonal canonical species-neutral ontologies: Molecular function - dependent continuants Biological process - occurrents Cellular component - independent continuants “Life is a process” Granularities of GO Molecular MF, BP, CC (Sub?)Cellular BP, CC Organismal BP Where will organismal functions live if we make CARO purely structural? GO working toward genus differentia definitions. GO is reference and application ontology. GO not is_a complete, is_a polyhierarchies Is_a diamonds usually due to multiple axes of classification, solution is to use genus differentia definitions and cross products. Example cysteine biosynthesis, cysteine is_a ereine family amino acid, and biosynthesis is_a metabolism. There is no need to create all the intermediates, easier just to make the cross product. Terms can be pre- or post composed - makes no difference as long as we adhere to genus differentia formalism Session II: Current state of model organism anatomy ontologies Melissa Haendel – MODs anatomy Model organism databases (MODs) use anatomy ontologies for annotation of gene expression or phenotype descriptions. Developmental stage, gene, and attribution are often recorded with an anatomy term. Ontologies facilitate annotation grouping. If MODs construct anatomy ontologies using the same principles, it will make cross-species comparisons easier. Developmental anatomy ontologies have multiple axes of classification: functional, spatial, developmental, structural, and developmental stage. Can CARO unify this organization? Relationships currently used in developmental anatomy ontologies: is_a, part_of, and develops_from. Developmental stage has been represented in MODs anatomy ontologies differently. Zebrafish has stages as a separate ontology, from which stages are assigned to each type in the anatomy ontology. Mouse has precoordinated each stage with type. Flybase has grouped types by superstage whole organism. These representations of stage are a full spectrum, from no pre-coordination and a separate stage ontology, to full pre-coordination. There are already three different levels of anatomical granularity represented by existing anatomy ontologies: GO cellular component, cross species CL cell type, cross species Species specific gross anatomy Can CARO integrate these different levels of granularity? All about developmental stages: There are different staging series for different organisms A stage represents a period of time Stages may have defining morphological characteristics or be fiat in time Each anatomical structure has a stage range during which it exists. The hierarchical relationships between types are affected by stage assignments: A child must exist within the stage range of its parent if it has an is_a or part_of relationship. A child’s stage range must at a minimum overlap or abut the stage range of its parent with which it has a develops_from relationship. Why do we need CARO: 1. To facilitate cross-species queries, for example, similar phenotypes or gene expression 2. To help MODs build anatomy ontologies for better curation and query 3. To promote better data-mining within and between ontologies. i.e. species-specific anatomy, cellular and sub-cellular anatomy, processes, functions, stages, taxonomy Discussion points: 1. Are the relationships is_a, part_of, and develops_ from sufficient for our needs? Develops_from has not yet been finalized in OBO-REL. What other relationships are required? 2. How should the MODs and/or CARO integrate the three ontological granularities of anatomy represented thus far? 3. The human foundational model of anatomy (FMA) is a structural ontology which offers many advantages. Can CARO integrate the functional, spatial, developmental, and staged anatomy? 4. How many stage relationships are needed? How should they be defined? How will they be used? 5. How organismally diverse should CARO be? 6. How deep should CARO be? Chris Mungall – Formalizing developmental stages A stage is part of the lifetime of an entity, stages are occurrents, could make a video of a stage, photo of an anatomical continuant. Continuants participate in stages. Substages are part_of superstages Stages preceded_by other stages We might think of a stage as a part of the life of an entity projected onto an abstract timeline specific to the relevant entity type (Compare different types of sport (game, match) process; e.g. a soccer match is divided into first half, second half and extra time.) Can’t always determine when an anatomical entity is first or last instantiated because of natural variation between organisms or variation between subtypes. The solution is to make the following new relations: Starts_during_or_after Ends_during_or _before The relative information about when anatomical structures arise during development can be used to infer anatomical process relationships. Ex, neural tube development & neural plate development. David Sutherland Part 1: Intelligent grouping of curations and use cases Basic ambiguity in curation: When a curator uses an anatomy term X, say to record expression in X, do they mean expressed in all subtypes of X, or in some unknown subset of X. Both of these are common, but should be distinguished. Using integral_part has advantages: 2 flavors of part relationship: X part_of Y Y has_part X If both are true, then it is an integral_part USE CASE: If we were only using part_of then this is legal: leg ...is_a male prothoracic leg ...part_of sex comb ...part_of claw With integral_part, we are restricted to this: leg ...is_a male prothoracic leg ......integral_part sex comb ...integral_part claw Deductions: All legs have a claw as a part. Prothoracic leg is_a leg. ? Prothoracic legs have a claw as a part. Sex comb part_of leg How has_part helps us cope with basic ambiguity of curation: Gene 1 - expressed in X (subset) Gene 2 - expressed in Y If the only known part relationship between X and Y is: Y part_of X It is not safe to group these two curations - we don't know whether the curation to X was made because of expression in a type of X that has a Y as a part. X has_part Y Then these two curations can be safely grouped - all types of X have a Y as a part. Part 2: Representing Part Relationships Between Developing Structures Identity during development: 1. A structure can have different parts and different stages. 2. Shifts in identity (i.e. changes in name) will be based on intrinsic criteria. The integral_part relationship that works so well for representing adult part relationships, is incompatible with both of these aims – has_part with 1, and part_of with 2. This being the case, we need some type of integral_part relationship that is stage specific. This could work as follows:  SHAPE \* MERGEFORMAT  Time ( Y integral_part* X, where integral_part* works as integral_part but applies only during the time (stages) that both X and Y exist. i.e.- At the times (stage) during development that both X and Y both exist: All X have (some) Y as a part and all Y are part_of (some) X. Barry: It is clear that we need to define special time-dependent part_of and has_part relations. E.g. (already in the OBO-RO paper at http://genomebiology.com/2005/6/5/R46): A initial_part_of B =def. every A is such that it begins to exist as part of some instance of B). A initial_X-stage_part_of =def. every A is such that it begins to exist as part of some instance of B at a time when B is in X-stage. Possible alternative definition for has_part For Y has_part X: All instances of Y have some instance of X as a part during the stages that both X and Y exist. B develops_from A: If part of the definition includes A and B abut in time: there is no instance that is both A and B simultaneously, then we can use overlap between stages to specify a range during which a transition occurs. For example: term X te=n ~ term Y ts=n+1 (note ts>n+1 would not be legal) Implies that the transition from X to Y occurs at the stage transition. term X te=n ~ term Y ts <=n Implies that the transition from X to Y occurs at some point during the overlap in stages between X and Y. Using cardinality in part reasoning: Grouping curations when we only know Y 'part_of' X is actually only an issue when there are subtypes of X . **Action Item – White paper on what relations are needed for development. Needed for this are use cases. Tom, Fabian, David and Chris will work on this. Haven’t discussed functional characterization of anatomical structures. Session III: CARO a common anatomy reference ontology Fabian Neuhaus- Review where we are so far One is_a hierarchy, AND CARO should be structural. But, need functions, and developmental terms. CARO needs supplementation with function ontology. Chris- I need ‘eye’ in CARO, but if eyes are defined only structurally, there wouldn’t be an eye in CARO. Cornelius Rosse- The Foundational Model of Anatomy (FMA) as a Template for CARO Theories of biology- hypothesis New science- ontology Unifying theory of structural phenotype an ontology artifact foundational model generalizes to mammalian/vertebrate/metazoan species Melissa- Why are boundaries/lines not anatomical structures? For example, the midbrain-hindbrain boundary, a site of gene expression. Answer, this is not really a line, but rather a 3D structure composed of a plane of cells. Even a line of cells is 3D so qualifies as an anatomical structure. What is the relationship between the midbrain-hindbrain boundary and a line or plane? Melissa- FMA foundational to represent multiple vertebrates, but doesn’t have homology. How then is it foundational in this sense? Part relations are secondary in an ontology, anatomists must make the switch from this kind of thinking if they are to use ontologies. The FMA: Consistent context Representation of different levels of granularity High class level in a taxonomy Definitions Selective propagation of attributes and relationships Michael- different granularities Melissa asks to examine the FMA for CARO/species independency after a brief homology review. Melissa Haendel - Homology Review Definition: Structures (including genes) are homologous if they evolved from some structure in a common ancestor Things that are functionally similar but don’t satisfy the above criteria are analogous. Example- Human parietal bone and zebrafish frontal bone are homologous. The zf and human frontal bones may be similarly located and may even have similar functions, but different genes and different developmental processes may underlie their development. They are synonyms, but not homologs. How and where should homology info be captured? Similar to how the MODs capture gene orthology. Homology assignments need evidence (codes) and attribution. Homology assignments are used to create and refine phylogenies. There are many homologous structures already implicit within MODs ontologies. Paula- The zebrafish anatomy ontology doesn’t seem to have any zebrafish specific types, they are all cypriniforme/vertebrate etc. Discussion points: 1. Do we need a relationship in OBO-REL to define homology? This is a symmetric relation between sisters and it is the relationship that requires evidence and attribution. 2. Should homology assignments be a top-down or bottom up approach? eg. Pairs of taxa vs. CARO-centric assignments? RE:domain experts are required. It might be easier to enlist help in a pairwise manner. 3. Homology needs to be captured for similarity searches. Text or synonym searches are insufficient. Does CARO take into account homology or is it a separate data set? 4. If two structures are deemed homologous, how does this information transfer down is_a chains? Need use cases. Cornelius Rosse- more analysis of the FMA with respect to CARO Is_a single type of structure Don’t belittle how homology affects parts and other relations. Go through the FMA, and change definitions and ask the question, are things still true if…? Cornelius- Separate what from how. Then address what needs to be done and who. Example- Gall from plant. Is it an anatomical structure? Another organism induces but it is made from organisms own genes. Similar example, wart. Inherent 3D shape, contiguous. ** New definition of anatomical structure: Material anatomical entity which has inherent 3D shape and is generated by coordinated expression of the organism's own genome. (Deleted structural, use genome instead of genes, remove its parts are spatially….) Raven- Should we have asexual species vs. sexual species? No-this is taxonomic. David OS: Does ‘inherent 3D shape’ imply that the entity in question must be contiguous and if so can this apply to organ systems? Cornelius: Yes David OS: So we can have organs systems in CARO, just not functional systems Cornelius: Yes Tissue- seems everyone is happy with ‘portion of tissue’. FMA Organ - Anatomical structure, which consists of the maximal set of organ parts so connected to one another that together they constitute a unit of macroscopic anatomy, structurally distinct from other such units. FMA Cardinal Organ part - Anatomical structure, which consists of two or more types of tissues that form a defined structural aggregate in an organ. We decided to delete “aggregate in an organ’. We also discussed adding “has as its discrete parts…” Much conversation about definitions of organ. Neuromast example – a case where different cell types but not different portions of tissue comprise an organ. Another example – the fly fat body, thought of as an organ but only one tissue type. FMA definition of ‘organ’ may especially not work for simpler organisms. Change to cardinal organism part, rather than cardinal body part. Body means different things to different communities. Discussion of FMA definition of ‘portion of tissue’, and whether it may apply to developing structures. FMA- portion of tissue: Anatomical structure, which consists of similarly specialized cells and intercellular matrix, aggregated according to genetically determined spatial relationships. The problem is ‘similarly specialized’, which many early structures, such as primordium and anlage, are not. This issue requires further discussion. Mesenchyme. Portion of mesenchyme, mass noun. Yet to consider- developing organ system, developing functional system, developing organ. Can CARO go deeper than these high level terms? A test with eyes and hearts. Organ Cavitated organ Heart Three chambered heart Two chambered heart Etc. Cavitated Eye Solid organ Solid eye Definition of heart from FMA discusses continuity with arterial and venous trees, this does not apply to the fly heart which is an open system. Also eye spots, which are not really organs by the FMA definition. The question is, if we take CARO to this level and only have structural definitions, will we be able to adequately represent all organisms? For the committee to discuss. ‘Adequately’ for some purposes, surely. But of course not for all purposes. Also needed is an organismal functional ontology FO (who will do this, GO?? Should be an extension of GO’s MF ontology to high granularities – BIRN, etc., already beginning work on this) This will allow grouping of anatomical structures by things like function=blood pumping. Short digression about incorporating cell types into anatomy. This has similar long term implications for addressing the different levels of granularity in CARO. See Chris’ document describing this at:  HYPERLINK "http://www.bioontology.org/wiki/index.php/CL:Aligning_species-specific_anatomy_ontologies_with_CL" http://www.bioontology.org/wiki/index.php/CL:Aligning_species-specific_anatomy_ontologies_with_CL Session IV: David Sutherland – Classifying developmental structures and giving them a home in CARO. GENUS: For developing structures to have a home in CARO, they need to be classifiable structurally using high level CARO terms. Contiguous developing structures can, at least prior to extensive structural differentiation, be classified as ‘portion of tissue’ within CARO. Terms that group many developing structures, e.g.- developing gut or developing digestive system, can be classified within CARO as ‘anatomical set’ or ‘anatomical cluster’ DIFFERENTIA: We need to work out whether/how developing structure terms can have a single differentia that allows disjoint is_a siblings under the relevant CARO structural classifications. We could to classify developing structures by lineage/fate on the cellular level. This is a traditional method of classification within developmental biology. If we are interested in continuity of developing structures, then I don't see any choice but to identify those at the cellular level (or at least per nucleus in a syncytial blastoderm). We should be careful not confuse this with gene expression domains as these can move in the absence of cell movement. Conversely, cells can move in and out of gene expression domains. [Note – Peter Vize disagrees with this focus on lineage/fate at the cellular level as opposed to focusing on domains defined by gene expresssion – we could ask him for an account of how he thinks this should work] This classification gives us 2 obvious differentia: Is the fate of all the cells in the developing structure predictable, or can their fate only be defined in terms of some high probability of contributing to specific adult structures. Does the structure in question contribute to one or many types of adult structure. (See slides for proposed detailed definitions of terms) Peter Vize: Some arguments against classifying structures based on lineage or fate mapping: cells are not structurally a probability of what they will become later on, they are physically part of an early tissue. In a structural anatomy ontology, they should be typed as an early tissue. The only way to define early tissue boundaries is gene expression patterns. However, borders of a gene expression domains don’t always map to a future tissue border. Lineage tracing is a very malleable thing and no two samples are alike in any embryo with any migration or cell mixing. Like fate mapping, lineage tracing can't be used in a mammal to define what tissue a cell will contribute to. So why include it in a reference AO? One solution would be to use a combination of part_of and develops_from relationships to define the early tissue. For example, a primordium such as the non-involuting marginal zone, is a part_of the ectoderm, and the spinal cord develops_from the non-involuting marginal zone. One could also add modifiers like anterior and posterior and therefore define exactly the region necessary. If not- define it using some anatomical basis, for example, zones of coordinated movement during gastrulation. Classification by these methods would facilitate mapping between species. Session V: Future Steps (Smith) Committee for CARO: Melissa, David, Fabian, Onard, Terry, Paula and Chris. They will see what steps need to be taken to bring better commonality using CARO as a guideline. **Action item- The committee will write a paper about CARO intentions. Form email list. **Action item: The upper FMA will be provided to the MODs in obo format. **Action item: Funding resources - Michael and Suzi have already notified Peter Good about this need. MODs that will use CARO + relationships and principles to build anatomy ontologies in some cases ab initio (a show of hands): Amphibians – Anne Maglia Cyprinoforme fishes – Paula Mabee Hymenoptera bees, wasps, ants – Neil Sarkar Zebrafish – Melissa Haendel Drosophila – David Sutherland FMA? Onard Mejino (Cornelius seemed convinced, but Onard was not present) Wormbase? Raymond Lee (had already left) MGI? Terry Hayamizu (may not change in-house ontology construction but will work towards being CARO compliant and providing a similar ontology view) Dictyostelium? – Rex Chisholm (I think was convinced but did not see his hand) Levels of anatomy granularity: Organism: population, organism, cardinal organism part Organ: organ complex (system), organ, organ part Cell: cell complex (portion of tissue), cell part (CC:GO), cell Molecule: molecule complex, molecule, molecule part In each case we are dealing with types – thus the kind of ontology we need under the heading ‘organism’ is an NCBI taxonomy; the kind of ontology we need under the heading ‘cell’ is the CL Cell Type ontology. **Action item - work with CL and GO to coordinate definitions and integration of cellular component, subcellular component, extracellular component, cell, etc. (already underway) For CARO committee - Add anatomical set children **Action item- anatomy listserve tissue/organ discussion. The BIG outstanding issue, anatomy terms in GO still can’t be cross-products with CARO. 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