Ontologies that describe the anatomical structures and cell types of model organisms are critically required for the annotation and successful exploitation of high-throughput datasets. The Uberon ontology (for anatomical structures) and the Cell Ontology (CL, for cell types) jointly aim to provide a consistent ontology that can be used across a wide range of species, by leveraging existing species-centric anatomy ontologies to construct a single integrated multi-species ontology. In this paper, we describe how we overhauled the integration mechanism between Uberon, CL, and the species-centric ontologies by using the newly devised SSSOM (“Simple Standard for Sharing Ontological Mappings”) standard to manage the mappings between all concerned ontologies.
One of the prerequisites for the reuse and reanalysis of datasets from high-throughput experimental
methods – such as single-cell RNA sequencing datasets – beyond their lab of origin is the annotation
of samples and results with standardised terms. That is, we need controlled vocabularies to properly
record information such as the exact techniques used, the organs or tissues from which the experimental
samples were taken, or the cell types that were identified. Several ontologies have been developed
for this kind of purpose, such as the Experimental Factor Ontology (EFO) to annotate experimental
methods [
However, comparing datasets across species additionally requires that the ontology terms used to annotate the datasets are themselves comparable. For example, comparing a dataset of mouse blood cells with a dataset of fly hemocytes requires that some link (relationship) exist between the term representing the concept of blood in mice and the term representing the concept of hemolymph in flies. Ideally, this would in turn require that a single cross-species ontology be used for all datasets, containing all the terms needed to represent all anatomical structures and cell types with their species-specific variations, organised in a consistent hierarchy.
Building a single cross-species anatomy ontology from the ground up, with terms suitable for all the
model organisms, would be a gigantic task, requiring lots of species-specific expertise that would be hard
to gather in a single project. Instead, a more practical approach was adopted by the Uberon project [
CEUR
ceur-ws.org
ontology with the species-specific ontologies along with the corresponding bridges is a product called
composite-metazoan (hereafter CM), a single, consistent cross-species ontology. The Cell Ontology (CL),
an ontology of cell types, follows the same approach [
To implement this strategy, Uberon maintains a set of cross-ontology mappings, which are used to determine where the terms from the species-specific ontologies should be placed in the overall Uberon hierarchy. Across ontologies of the OBO Foundry, the typical method to represent and maintain mappings is to use cross-references (or, informally, “xrefs”). It’s a very simple method where, to map a term in an ontology A to a term in a foreign ontology B, is annotated with a oboInOwl:hasDbXref property, whose value is the short identifier (“CURIE”) of . As part of the Uberon release pipeline, a Perl script automatically extracts those cross-references and generates the bridge files needed to integrate the species-specific ontologies.
While simple, the cross-reference method has several limitations. (i) It does not allow to record any metadata about the mapping, such as: who asserted that the two terms should be mapped? On what basis? When was the mapping reviewed? (ii) The method does not allow for any nuance: either two terms are mapped or they are not, without room to express more subtle relations. (iii) Cross-references are embedded within the ontology itself, and are therefore not easily reusable by third parties. (iv) Cross-references have no clear and universally agreed upon meaning. When two terms are mapped to each other, the meaning of the mapping is left unspecified, and typically has to be inferred from the ontologies that are being mapped (for example, a mapping between the species-neutral Uberon and the Drosophila-specific FBbt can be inferred to be a cross-species mapping). This is made worse by the fact that cross-references in OBO ontologies are used for many diferent things beyond just mappings; for example, when used to annotate a term definition, cross-references typically attribute a source for the definition, akin to a citation in an academic paper.
We have devised a new approach to maintain and use cross-ontology mappings in Uberon, centred around three axes: (i) the use of a new format to represent the mappings, (ii) the creation of dedicated mapping relations, and (iii) the development of new tools to manipulate the mappings and, in particular, derive OWL axioms from them.
The Simple Standard for Sharing Ontological Mappings (SSSOM) is a recently devised standard
specifically intended to facilitate the exchange of semantic mappings [
One of the benefits brought by the SSSOM standard is the possibility to use highly specific mapping
predicates to express precisely the intended meaning of a mapping. While many mapping sets don’t
actually need this, and can use common mapping predicates such as those from the SKOS vocabulary [
Overall we believe that cross-species mappings are sui generis mappings and that they warrant the
use of dedicated mapping predicates to reflect that fact. We therefore expanded the SEMAPV vocabulary,
specifically established for use with SSSOM [
Even as SSSOM adoption spreads rapidly, it is likely that many tools will remain unable to directly
exploit SSSOM sets in the foreseeable future. Therefore, when mappings are stored in the SSSOM format,
we need to be able to convert them into OWL axioms that can be used by any ontology manipulation
tool. To that efect, we have developed a SSSOM plugin for ROBOT, the standard tool used to manipulate
OBO ontologies [
Rather than hardcoding the logic for deriving the axioms – which would have been eficient but would have made the logic harder to modify and re-use – we designed a small domain-specific language (DSL), named SSSOM/T-OWL (“SSSOM/Transform-to-OWL”), that allows users to describe which mappings in a set should be transformed into OWL axioms and what kind of axioms should be produced.
The SSSOM/T-OWL language is organised around the single concept of “transformation rules”. A rule is made of two elements (Table 1): a filter (or selector) to decide whether the rule should apply to a given mapping; and either a preprocessor, to modify a mapping on the fly, or a generator, to produce a OWL axiom from the mapping.
Filters allow the value of any of the SSSOM metadata slots to be compared with a target value and to discard any mapping with a diferent value. A basic form of wildcard matching is supported, where a iflter can select mappings with a value that starts with the same prefix as the target value. Individual iflters can be combined to select mappings based on more than just one metadata slot; they can also be negated, so that a filter that would select a given set of mappings would, after negation, instead select the complementary set of mappings.
Preprocessors allow a mapping to be modified before it is used by subsequent rules. Possible modifications include inverting a mapping (the subject becomes the object and vice-versa) and changing some of the mapping’s metadata. A preprocessor can also be used to completely remove a mapping from the set, so that no further rule will be applied to this mapping.
Finally, the generators take the selected mapping and turn it into an axiom. The most important
generator function is create_axiom, which can produce an arbitrary axiom described by an expression
in Manchester syntax [
Of note, the current implementation of the SSSOM/T-OWL language cleanly separates the OWL generators from the filters and the preprocessing functions. This makes it easy to create other domainspecific languages similar to SSSOM/T-OWL, using the same overall syntax, the same filters and the same preprocessors, but that generate objects other than OWL axioms.
With the components described in the previous section in place, we overhauled the pipeline that builds Uberon’s composite-metazoan product (Figure 3).
Rather than migrating all of Uberon mappings to SSSOM at once, we have adopted a phased approach, in which we have used the mappings between Uberon and FBbt as a test bed in a preliminary phase. Uberon/FBbt mappings were initially maintained as cross-references within Uberon, as for all the other Uberon mappings. We migrated them to a SSSOM mapping set that we now maintain on the FBbt side: existing FBbt cross-references in Uberon were extracted from the ontology and converted into SSSOM mappings using the newly minted semapv:crossSpeciesExactMatch predicate (all existing cross-references were for exact mappings, since that was the only kind of mapping allowed by the cross-reference system), that are now published alongside the FBbt ontology itself.
Mappings between Uberon and the other species-specific anatomy ontologies beyond FBbt are still currently maintained as cross-references either within Uberon or within the species-specific ontologies. They are extracted and converted to SSSOM dynamically as part of Uberon’s release pipeline. In a second phase, which we have not started yet, we will migrate those mappings fully to SSSOM, as was done for the FBbt mappings.
Regardless of their origin, all mappings between Uberon, CL, and the species-specific ontologies are processed by a single large SSSOM/T-OWL ruleset that contains all the required logic to generate the bridging axioms. A typical rule in this ruleset is the following: ( s u b j e c t ==UBERON : ∗ | | s u b j e c t ==CL : ∗ ) && o b j e c t == F B b t : ∗ && p r e d i c a t e == semapv : c r o s s S p e c i e s E x a c t M a t c h −> c r e a t e _ a x i o m ( ’ % o b j e c t _ i d E q u i v a l e n t T o : % s u b j e c t _ i d and ( BFO : 0 0 0 0 0 5 0 some NCBITaxon : 7 2 2 7 ) ’ ) ;
That rule can be literally understood as: a mapping between a Uberon (or CL) term and a FBbt term and that uses the semapv:crossSpeciesExactMatch predicate must be transformed into an equivalence axiom that states that the FBbt term is equivalent to the intersection of the Uberon (or CL) term and an existential restriction over BFO:0000050 (‘part of’) and NCBITaxon:7227 (‘Drosophila melanogaster’).
All axioms produced by the SSSOM/T-OWL ruleset are saved into a separate bridge file for each foreign ontology.
Once the bridge files have been generated, an intermediate ontology ( collected-metazoan) is built by merging together Uberon itself, the Cell Ontology, all the species-specific ontologies, and their corresponding bridges. Finally, composite-metazoan itself is derived from this intermediate product by applying some custom logic (implemented in a small, dedicated ROBOT plugin) to “prune” redundant terms and replace them with equivalent anonymous class expressions.
The details of this last operation are beyond the scope of this paper, but as an example, let us consider the FBbt term ‘ovary’ (FBbt:00004865): it is mapped to the Uberon term ‘ovary’ (UBERON:0000992), so collected-metazoan contains the following axiom: F B b t : 0 0 0 0 4 8 6 5 E q u i v a l e n t T o : UBERON : 0 0 0 0 9 9 2 and
( BFO : 0 0 0 0 0 5 0 some NCBITaxon : 7 2 2 7 )
The “pruning” operation leading to composite-metazoan consists of replacing all occurrences of FBbt:00004865 by the anonymous expression it is equivalent to. So the following axiom, which states that the ‘oviduct’ (FBbt:00004911) is ‘continuous with’ (RO:0002150) the fly ovary: F B b t : 0 0 0 0 4 9 1 1 S u b C l a s s O f : RO : 0 0 0 2 1 5 0 some F B b t : 0 0 0 0 0 4 8 6 5 gets rewritten as:
F B b t : 0 0 0 0 4 9 1 1 S u b C l a s s O f : RO : 0 0 0 2 1 5 0 some ( UBERON : 0 0 0 0 9 9 2 and ( BFO : 0 0 0 0 0 5 0 some NCBITaxon : 7 2 2 7 ) ) In this project, we have (i) expanded the SEMAPV vocabulary so that cross-species mappings can be specifically represented in SSSOM; (ii) introduced a domain-specific language (SSSOM/T-OWL) to allow converting SSSOM mappings into arbitrary OWL axioms; (iii) implemented said language in a new ROBOT plugin to inject SSSOM-derived axioms into a OWL ontology; (iv) used those new tools to update the integration mechanism between Uberon, CL, and the species-centric ontologies, with an approach centered on the use of SSSOM, rather than cross-references, to manage the mappings between the ontologies.
As a result, cross-species mappings across anatomy ontologies are now available as a bona fide release artefact of Uberon, provided as a distinct file in a known location in a standard format, thereby greatly facilitating the reuse of said mappings by any interested third party. The logic for deriving the bridge ifles (needed to correctly merge Uberon and the species-specific ontologies), now expressed in the SSSOM/T-OWL language, is itself consequently more easily maintainable and reusable.
While several aspects of this project (most notably the precise SSSOM/T-OWL rules we use) are specific to the needs of Uberon, we believe the general approach of maintaining mappings as SSSOM sets and transforming them into OWL bridges using a simple DSL could be generalised to any project that requires integrating several ontologies together.
This work was supported by grant BB/T014008 from the UK Biotechnology and Biological Sciences Research Council (BBSRC) and the US National Science Foundation Directorate of Biological Sciences (NSF/BIO).