Cross Product Extensions to the Gene Ontology

Cross Product Extensions to the  Gene Ontology  Chris Mungall  Gene Ontology Consor8um  h:p://www.geneontology.org 

Outline  • What the Gene Ontology is used for  – GO structure  – Limita8ons of text deﬁni8ons  • Cross‐product extensions to the GO  – Logical computable deﬁni8ons  • Results and Examples  – Chemical en88es, proteins, cells  – Anatomy and development  – Rela8ons  – Reasoning  • Release Plan  • Conclusions 

A brief introduc8on to the GO  • Nearing 11th birthday  • 3 ontologies, 28k classes  – Molecular Func8on (MF)  – Biological Process (BP)  – Cellular Component (CC)  • Annota8ons  – 42m statements assigning func8on or localiza8on to genes across 187k species   • Standard uses of GO annota8on:  – Naviga8ng and querying func8onal annota8ons for genes  – Discovery; term enrichment; seman8c similarity  – >50 tools for performing hi‐throughput analysis using GO  • Most uses require a simple, lightly axioma8zed graph  – is_a  – part_of  – Deﬁni8ons are textual 

Problems and limita8ons   • Maintenance and  errors  – Combinatorial terms  – Tangled  polyhierarchies  • Denormalized  – Redundancy   – lack of reuse 

Solu8on: normaliza8on + reasoning  • Prior work  metabolism sulfur amino acid – Rector et al  x  – Hill et al  biosynthesis cysteine • Retrospec.ve  sulfur amino normaliza8on  acid metabolism – GO preceded OBO  • How?  cysteine sulfur amino acid – GONG, Wroe et al  =  metabolism biosynthesis – Ogren et al  – Obol  cysteine biosynthesis

Assigning logical defini8ons to GO  classes  • Logical defini8on structure  – An X is a G that D  • X : defined term  • G : genus (parent) term  • D : differen8a(e) – discrimina8ng rela8onships  – Necessary and sufficient condi8ons  – Computable defini6on should mirror text defini6on  • Simple formalism, limited expressivity  – Equivalence axioms between named classes and posi8ve conjunc8ons  of named class and one or more existen8al restric8ons  • OBO priniciple of Posi.vity  – General template:  • EquivalentClasses(NamedClass intersec8onOf(NamedGenus  [someValuesFrom(NamedObjectProperty NamedDifferen.aClass)]+)) 

Example: mitochondrial transla8on  • ‘mitochondrial transla8on’ =def ‘transla8on’ that  occurs_in ‘mitochondrion’  – (current rela8onships in GO are necessary condi8ons  only)   OBO  id: GO:0032543 name: mitochondrial translation intersection_of: GO:0006412 ! translation intersection_of: occurs_in GO:0005739 ! mitochondrion FOL  X instance_of ‘mitochondrial transla8on’ <‐>    X instance_of transla8on &     exists C,t [ C instance_of mitochondrion at t & X occurs_in C at t ]  OWL  Class: ‘mitochondrial transla8on’  manchester  EquivalentTo: transla8on AND occurs_in SOME mitochondrion  syntax 

Cross Product (XP) Sets  • GO has ~28k classes  – Retrospec8ve assignment of logical deﬁni8ons is a lot of work  – Divide work according to ontologies directly used  • Cross Product par88ons  – X   <O1 x O2 x .. x On >   • typically n=2  • Genus taken from O1  • Diﬀeren8ae taken from O2..n     – Example: BP:cysteine_biosynthesis   <BP x CHEBI>  • BP:biosynthesis that has_output CHEBI:cysteine   – Each XP set has one or more templates  • Obol grammars  – h:p://wiki.geneontology.org/index.php/Category:Cross_Products 

Results: Logical deﬁni8ons per XP set  Genus  MF  BP  CC  13k classes have  MF  103  241  148  provisional logical  deﬁni8ons (46% of classes)   BP  4046  27  CC  634  289  cell  541  25  anatomy  692  chemical  7278  3072  protein  37  quality  0  sequence  66  RNA  0 

GO Class  Logical Defini6on  Genus  Differen6a  Ontology  ontology(s)  S phase of mito6c  S phase  and part_of mitosis   BP  BP  cell cycle   mitochondrial  transla6on and occurs_in mitochondrion   BP  CC  transla6on  Oocyte  cell differen6a6on and  BP  CL  differen6a6on   results_in_acquisi.on_of_features_of  oocyte   Neural plate  anatomical structure forma6on and  BP  anatomy  forma6on   results_in_forma.on_of neural plate   Interleukin‐1  biosynthe6c process and has_output  BP  PRO  biosynthesis   interleukin‐1   L‐cysteine  catabolic process and has_input L‐ BP  CHEBI  catabolic process  cysteine and has_output taurine   to taurine   group I intron  catabolic process and has_input group I  BP  SO/RNAO  catabolic process   intron  

GO Class  Logical Deﬁni6on  Genus  Diﬀeren6a  Ontology  ontology(s)  histone  protein complex and has_func.on  CC  MF  deacetylase  histone deacetylase ac6vity   complex   acrosomal  membrane and surrounds acrosome   CC  CC  membrane   neuron projec6on  cell projec6on and part_of neuron  CC  CL  virion transport  transport vesicle and realizes vesicle  CC  BP  vesicle  transport  snoRNP binding  binding and results_in_binding_of   MF  CC  snoRNP  methionine  cataly6c ac6vity and   MF  CHEBI  synthase ac6vity  has_input  5‐methyltetrahydrofolate  and has_input  L‐homocysteine and  has_output  tetrahydrofolate and  has_output  L‐methionine 

Nested logical defini8ons  • Mul8ple differen8ae and nested descrip8ons  allowed  – Only named classes used  – Spans XP sets  GO Class  Logical Defini6on  Genus  Differen6a  Ontology  ontology(s)  nega6ve regula6on  biological process and  BP  BP  of RNA metabolic  has_par.cipant RNA  process  metabolic process  RNA metabolic  metabolic process and  BP  CHEBI  process  has_par.cipant RNA 

Development and anatomy  • Neural plate forma6on = anatomical structure  forma6on and results_in_forma.on_of neural plate  – GO annota8ons to xenopus, zebraﬁsh, mouse  • Where is neural plate declared?  – Developmental structures not in scope of FMA  – Other choices:  • EHDAA – mouse (TS1‐26)  • ZFA ‐ zebraﬁsh  • TAO ‐ teleost  • XAO ‐ xenopus  – Gross anatomical ontologies are species‐or‐taxon‐centric  

Uberon: a mul8‐species anatomy  ontology  • GO contains an implicit anatomy ontology spanning mul8ple species  – GO:0007423 ! sensory organ development  • GO:0001654 ! eye development    – GO:0043010 ! camera‐type eye development  – GO:0048749 ! compound eye development  sensory organ  • Normalized to form Uberon  development  – Alignments with species‐centric AOs  – 3000 classes  – See Poster  • Current XP par88oning:  eye  development  – Uberon [most metazoa]  – PO [plants]  – Others  • Fungal anatomy ontology  • Dictyosteliam anatomy ontology  compound eye  camera‐type  development  eye  development 

Addi8onal rela8ons are required for  full XP set  • Core RO  – part_of, has_par.cipant  • Spa8al rela8ons (CC x {CC,CL})  – membranes, pores  – adjacent_to, surrounds, perforates  • Par8cipa8on rela8on subtypes  – has_input, has_output  – ‘macro’ deﬁned rela8ons  – E.g. results_in_transport_{of,to,from} 

Reasoning  • Reasoning used as part of ontology development cycle  – batch mode  – interac8ve in OBO‐Edit2  – pre‐reasoned: inferred rela8onships are asserted  • Scalability  – GO + XPs + Referenced ontologies = 130k classes  – In memory reasoners do not scale  – h:p://wiki.geneontology.org/index.php/OBO‐ Edit:Reasoner_Benchmarks  – Solu8ons:  • Segmenta8on by XP set  • CHEBI slim  • RDBMS based reasoning 

Reasoner results  • 1000s of links fixed over number years  • inconsistencies internal to GO fixed immediately  – Fix hierarchy of defined class  – Fix hierarchy of referenced class  • abduc8ve reasoning (Bada et al OWLED 2008)  – Fix logical defini8on  • inconsistencies external to GO take longer to be  resolved  – CL  – CHEBI 

BP x CHEBI example  transport  carbohydrate  is_a  is_a  is_a  carbohydrate  nucleo6de,  carbohydrate  phosphates  nucleobase or  transport  nucleoside  cabrohydrate transport =def transport  is_a  transport  and results_in_movement_of  nucleoside  carbohydrate  phosphates  is_a  is_a  nucleo6de  nucleo6des  transport  nucleo6de transport =def transport and  results_in_movement_of nucleo8de 

Release plan: basic and extended  releases  • GO is currently available in two versions  – gene_ontology: “standard”  • is_a, part_of, intra‐ontology regulates  • intended for basic tools  – gene_ontology_ext: “extended”  • h:p://www.geneontology.org/GO.ontology‐ext.rela8ons.shtml  • standard + other rela8ons and axioms  – disjoint_from  – has_part (Aug 1 2009)  • XP sets current available as separate bridge ﬁles  – h:p://wiki.geneontology.org/index.php/ Category:Cross_Products  – will gradually migrate into gene_ontology_ext  

Pre vs post composi8on  • Compose class descrip8ons  – During ontology development cycle?  – At the 8me of annota8on?  • Logically equivalent…  – Given computable defini8ons, reasoners can determine equivalency  • .. But very different from prac8cal point of view  • GO guidelines  – pre‐compose classes for any type for which scien8fic generaliza8ons  can be made  • Yes: mitochondrial transla8on  • Yes: oocyte nucleus  • No: nucleus of epithelium of le~ ear    – Use post‐composi8on to extend at annota8on 8me   

Related work: weaving the fabric of  the OBO Foundry  • Ontology for Biomedical Inves8ga8ons (OBI)  • Phenotype Ontologies  – Mammalian Phenotype  – Human Phenotype  – Worm Phenotype  – Plant trait  • Environment ontology  • FMA  • Fly anatomy ontology  – Neuronal subtype and sense organ logical deﬁni8ons using  CHEBI and GO 

Future applica8ons of cross‐product  sets  • Demonstrated u8lity as part of ontology development cycle  – How do we evaluate?  – but what about actual applica8ons?  • How can logical deﬁni8ons (and addi8onal axioma8sa8on in  general) help:  – Search and discovery  – Visualiza8on and presenta8on to users  – Cura8on  – Improve func8on predic8on  – Database integra8on  • E.g. pathway databases  – Term enrichment  – Seman8c similarity  • Need to educate tool developers 

Conclusions  • Normalizing retrospec.vely is hard  – Prospec.ve approach recommended  – But redundancy in eﬀort from alterna8ve perspec8ve can yield  valuable informa8on  • Many of the challenges are sociotechnological  – What if the referenced ontology  • does not yet exist?  • exists but is unfunded?  • is constructed according to diﬀerent principles?  • is incomplete?  • ..or there is a choice of two compe8ng ontologies?  – The OBO Foundry process is crucial  • Grant challenge: more applica8ons needed 

Acknowledgments  • GO Ontology Developers  • OBO Ontology developers  – Midori Harris  – Alex Diehl (GO, Cell)  – Janna Has8ngs (CHEBI)  – Jane Lomax  – Paula de Matos (CHEBI)  – Jen Deegan  – David Osumi‐Sutherland (Fly)  – Amelia Ireland  – Melissa Haendel (Zebraﬁsh)  – Tanya Berardini  – Darren Natale (PRO)  – David Hill  – Karen Eilbeck (SO)  • Also  • OBO‐Edit  • Amina Abdulla  – Mike Bada  – Colin Batchelor  • Nomi Harris  • John Day‐Richter  • OBO  • GO PIs  – Alan Ru:enberg  – Suzanna Lewis  – Barry Smith  – Mike Cherry  – Richard Scheuermann  – Michael Ashburner  – Judith Blake 

Cross Product Extensions to the Gene Ontology

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