Phenotype annotation using ontologies Chris Mungall (+ BS) Berkeley Bioinformatics and Ontologies Project (BBOP) National Center for Biomedical Ontology (NCBO)

A biological ontology is:  A precise representation of some aspect of biological reality eye  what kinds of things exist?  what are the relationships between these things? ommatidium sense organ eye disc is_a part_of develops from

OBD Foundry definition of a phenotype  A collection of qualities inhering in one or more entities  Examples:  the quality of being reduced mass inhering in bone (i.e osteoporosis)  the quality of being hypoplastic inhering in a midface  the quality of lacking asters inhering in spermatocytes  Qualities are real and have spatial or spatiotemporal extent

PATO : qualities  Purpose:  originally for annotation of mutant phenotypes  now: OBO Foundry candidate reference ontology for biological qualities  Both spatial and spatiotemporal attributes  shape (inheres in a 3D object)  rate (inheres in a process)  Multiple levels of granularity

Old EAV representation EntityAttributeValue eyesizesmall heartstructureedematous ventral mandibular arch thicknessthick swim bladder inflation process attribute arrested PATO AO GO, CLO, … PATO

Problems with EAV EntityAttributeValue organismeatspeanut butter and jelly sandwiches skinreddark skincolorred heartshapeheart-shaped What is attribute, what is value? Every attribute is turned into a relation?

Towards a Single Hierarchy of Monadic Qualities  long length is_a length  hot temperature is_a temperature  cylindrical shape is_a shape  extended cylindrical shape is_a cylindrical shape ontologies are about types; values reflect a confusion between types and instances

New Quality Ontology BearerQuality eyesmall [size] heartedematous [structure] ventral mandi- bular arch thick [thickness] swim bladder inflation arrested [process] CARO, GO, CL, … PATO

Extensions  E+Q is not enough in itself  Relational attributes  Relative attributes  Measurements  the measurement is not the phenotype

Relational attributes  Most qualities are monadic  they inhere in a single self-connected entity  e.g. shape, color  Some qualities are relational (instance-to-type)  they inhere in >1 entity  e.g. sensitivity, tolerance  Some qualities are relative (instance-to-instance)  e.g. taller_than  Soon PATO will indicate which qualities are relational

E+Q extended with secondary relata BearerQuality eyehigh [sensitivity]red light brainfused [structure]eye leg1longer_thenleg2

Problem of Lacks  Common attributes for systematics  spermatocyte devoid of asters  Example: wingless  E=wing, A=presence, V=absent  but there is no wing for the quality of absence to inhere in  Consider instead  The thorax (or whole fly) has the quality of being wingless =def. A normal thorax of this type has_a wing but not (this instance has_a wing) lacks is like instantiation: it relates instances to types

Ontological relations for anatomy and phylogeny  Basic set (from OBO relations ontology) is_a part_of  ontogenic/developmental derives_from transformation_of  New relations has [has_quality] lacks in_organism not_in_organism evolved_from homologous_to

Instances and types  Dictionary definitions leave lots of room for ambiguity  especially for relations  We must be careful to distinguish between instances and types when defining relations  We directly perceive and interact with instances  As scientists we are primarily interested in types  Type level relations are defined in terms of instances

is_a  also known as: subtype_of  X is_a Y  given any x that instantiates X at time t, x also instantiates Y at time t  informally: all Xs are always Ys  is_a is a transitive relation  if X is_a Y and Y is_a Z then X is_a Z  Examples:  left eyeball is_a eyeball  eye development is_a organ development  monotreme is_a mammal

eyeball cavitated organ is_a organ is_a instance_of types instances

part_of  X part_of Y (where X and Y are types)  given any x that instantiates X at time t, there exists some y at time t such that y instantiates Y and x part_of y  informally: all Xs are part of some Y at all times  part_of is a transitive relation  if X part_of Y and Y part_of Z then X part_of Z  Examples:  ommatidium part_of compound eye  male genital system part_of body  placenta part_of female reproductive system

ontogenic relations  OBO relations ontology defines:  transformation_of (single entity, identity preserving)  derives_from (fusion and fission)  Most OBO ontologies currently use develops_from  can be considered the union of transformation_of and derives_from  Transitive  Example:  T cell develops_from T lymphoblast  male reproductive organ develops_from gonad primordium  female reproductive organ develops_from gonad primordium

in_organism  X in_organism Y (where X and Y are types)  given any x that instantiates X at time t, there exists some y at time t such that y instantiates Y and x part_of y  informally: all Xs are in some organism of type Y  Examples:  vertebrate eye in_organism vertebrate  placenta in_organism mammal [discuss!]

not_in_organism  Features are often lost  X not_in_organism Y (where X and Y are types)  given any x that instantiates X at time t, there exists no y at time t such that y instantiates Y and x part_of y  informally: no Xs are in any organism of type Y  Examples:  ceratobranchial 5 tooth not_in_organism Gonorhynchiformes  To be added to OBO relations ontology  Do we need organism_lacks?  Warning: exceptions are bad for ontologies  how to deal with return of atavistic features?

eye vertebrate eyecompound eye is_a vertebratearthropod in_organism coelomata ommatidium part_of is_a