An Introduction to Anatomy Ontologies

Phenotype RCN Feb 23, 2012

Melissa Haendel

Setting the stage1. Who are we? What do we need? Why

are we here?2. What is an anatomy ontology?3. What kinds of anatomy ontologies

exist? 4. How are anatomy ontologies used?5. Anatomical evidence

Who are we? Domain Experts:Anatomists, comparative morphologists,developmental biologists, immunologists, neuroscientists, etc.

Ontologists:Biologists-gone-informatics, computer scientists and logicians

Engineers:Our tool builders

Domain experts: want to query for gene expression and phenotypes across species

Ontologists: have to be able to interpret and

represent domain knowledge

computationally

Engineers: have to build tools that can

consume ontologies and give the

Domain Experts the right results

Therefore, we build ontologies that are intelligible to:

Domain experts Machines

Comparison of structures across different organisms, scales Standardization of anatomical vocabulary among and between

communities Integration of anatomical data across databases Query across large amount of data Automatic reasoning to infer related classes Error checking Annotation consistency

We want to enable:

OntologistsEngineers

OMIM Query # Records

“large bone” 785

“enlarged bone” 156

“big bone” 16

“huge bones” 4

“massive bones” 28

“hyperplastic bones” 12

“hyperplastic bone” 40

“bone hyperplasia” 134

“increased bone growth” 612

Anatomical information retrieval from text-based resources

Less than ideal.

Why build an anatomy ontology? A simple example

Number of genes annotated to each of the following brain parts in an ontology:

brain 20part_of hindbrain 15part_of rhombomere 10

Query brain without ontology 20Query brain with ontology 45

Ontologies can facilitate grouping and retrieval of data

There are many useful ways to classify parts of organisms:

its parts and their arrangement its relation to other structures

what is it: part of; connected to; adjacent to, overlapping?

its shape its function its developmental origins its species or clade its evolutionary history

Cajal 1915, “Accept the view that nothing in nature is useless, even from the human point of view.”

An ontology is a classification

appendage

antenna forewing

wing

hindwing

Relationships record classifications too

leg

part_of some ‘thoracic segment

wing

‘leg’ SubClassOf part_of some thoracic segment

It is difficult to keep track of multipleclassification chains to: • ensure completeness;• avoid redundancy;• Incorrect inheritance of classification

criteria from a distant superclass

Multiple inheritance is very hard to manage by hand

The knowledge in an ontology can make the reasons for classification explicit

Any sense organ that functions in the detection of smell is an olfactory sense organ

sense organcapable_of some detection of smell

olfactory sense organ

nose

sense organ

nose

capable_of some detection of smell

Classifying

sense organcapable_of some detection of smell

olfactory sense organ

nose

Compositionality and avoiding asserted multiple inheritance

We can logically define composed classes and create complex definitions from simpler ones

aka: building blocks, cross-products, logical definitionsDescriptions can be composed at any time

Ontology construction time (pre-composition) Annotation time (post-composition)

Formal necessary and sufficient definitions + a reasoner

Automatic (and therefore manageable) classification Requires subtype classification, so apart from the root

term(s), no term should lack an is_a parent.

Let the reasoner do the work!

Example of a post-composed anatomical entity

Plasma membrane of spermatocyte• Plasma membrane [GO CC]• Spermatocyte [Cell Ontology]

a plasma membrane which is part_of a spermatocyte

Gene Ontology Basic Formal Ontology Cell Ontology

Genus Differentia

chemical entities

Many perspectives, many ontologies

grossanatomy

tissues

cellscellanatomy

proteins

phenotypes

clinical disorders

processes

physiological processes

development

reactions

cellular processes

behavior

evolutionary characters

nervous systemneural crest

What kinds of anatomy ontologies exist?Mouse

MA (adult) EMAP / EMAPA (embryonic)

Human FMA (adult) EHDAA2 (CS1-CS20)

Amphibian AAO XAO

Fish ZFA (zebrafish) MFO (medaka) TAO (teleosts)

Nematode WBbt (c elegans)

Arthropod FBbt (Drosophila) TGMA (Mosquito) HAO (hymenoptera) Arthropod anatomy ontology

Plant ontology

Species-centric and multi-species ontologiesSpecies neutral ontologies

CARO (common anatomy reference ontology)

Uberon (cross-species anatomy)vHOG (vertebrate homologous organs)

CL (cell ontology)

GO (gene ontology)

Phenotype ontologies

MP mammalian phenotype

HP human phenotype

WB worm phenotype

Species-centric ontologiesThe Zebrafish Anatomy Ontology

Used to record gene expression and phenotypes at different stages of development

Ontologies built for one species will not work for others

http://fme.biostr.washington.edu:8080/FME/index.html

http://ccm.ucdavis.edu/bcancercd/22/mouse_figure.html

Multi-species anatomy ontologies

Seed plants(Angiosperms and

Gymnosperms)

Pteridophytes(Ferns and Lycopods)

Bryophytes(Mosses, Hornworts

and Liverworts)

Algae

Bowman et al, Cell, 2007

The Plant Ontology

Challenge is in representing diversity in anatomy, morphology, life cycles, growth patterns

Example of complexity arising from multiple species-contexts

erythrocyte

cell

nucleate cell enucleate cell

not applicable in all contexts

Example of complexity arising from multiple species-contexts

erythrocyte

nucleate erythrocyte

enucleate erythrocyte

cell

nucleate cell enucleate cell

zebrafish nucleate

erythrocyte

human erythrocyteZFA:0009256

… …

CL:0000562

CL:0000232

CL:0000592

FMA:81100

species ontologiesattached at appropriatelevel

Developmental Biology, Scott Gilbert, 6th ed.

Using reasoners to detect errors

Fruit fly FBbt ‘tibia’ Human FMA ‘tibia’

UBERON: tibia

UBERON: bone

is_a

is_a

is_a

Vertebrata

Drosophila melanogaster

part_of

Homo sapiens

is_a

only_in_taxon

part_of

disjoint with

✗

The Gene Ontology has an anatomy ontology

Look ma, no pons!

human

zebrafish

Phenotype ontologies also have inherent anatomy

Designed primarily for annotation of phenotypes within a single species

WBbt C. elegansphenotype

Representing different levels of granularity

lateral line development

?

?

cilium part_of hair cell part_of neuromast

hair cell part_of neuromast

neuromast part_of lateral line

GO

cilium development

hair cell development

neuromast development

lung

lung

respiratory gaseous exchange

lobular organ

parenchymatous organ

solid organ

pleural sac

thoracic cavity organ

thoracic cavity

multicellular organismal process

abnormal lung morphology

abnormal respiratory system morphology

GO

MPO

MA

FMA

abnormal pulmonary acinus morphology

abnormal pulmonary alveolus morphology

lungalveolus

respiratory system process

organ system

respiratory system

Lower respiratory

tract

alveolar sac

pulmonary acinus

organ system

respiratory system

EHDAA2

lung

lung bud

respiratory primordium

pharyngeal region

develops_frompart_of

is_a (SubClassOf)

surrounded_by

The problem: Data Silos

How to synchronize anatomy ontologies

Mapping Direct reconciliation Synchronization using imports/MIREOT

Three approaches:

There are issues with mappingsClass A Class B In Bioportal? Useful?

FMA extensor retinaculum of wrist

MA retina Yes No

FMA portion of blood MA blood No Yes

ZFA Macula MA macula Yes No

ZFA aortic arch MA arch of aorta Yes Dubious

ZFA hypophysis MA pitiuitary No Yes

FMA tibia FBbt tibia Yes No

FMA colon GAZ Colón, Panama Yes No

PATO male Chebi maleate 2(-) Yes No

Zebrafish terms are is_a subtypes of teleost terms

is_a

Zebrafish Anatomy Teleost Anatomy Ontology

Reconciliation and linking between TAO and ZFA

Logic implemented via Xrefs- difficult to keep synchronized

The Common Anatomy Reference OntologyCARO is a structural classification based on

granularity

From the bottom up:Cell componentCellPortion of tissueMulti-tissue structure

From the top down:Organism subdivisionAnatomical system

Acellular structuresNote: CARO is being updated to be more interoperable, include logical definitions, and functional differentia

Synchronization by import across ontologies

One can import a whole ontology or just portions of another ontologyMIREOT: Minimum information to reference an external ontology term

CARO

VAO

Present TAO Modularized ontology

Uberon – a multi-species ontology for phenomics and evo-devo analyses

Uberon.org

anatomical structure

endoderm of forgut

lung bud

lung

respiration organ

organ

foregut

alveolus

alveolus of lung

organ part

FMA:lung

MA:lung

endoderm

GO: respiratory gaseous exchange

MA:lung alveolus

FMA: pulmonary

alveolus

is_a (taxon equivalent)

develops_frompart_of

is_a (SubClassOf)

capable_of

NCBITaxon: Mammalia

EHDAA:lung bud

only_in_taxon

pulmonary acinus

alveolar sac

lung primordium

swim bladder

respiratory primordium

NCBITaxon:Actinopterygii

Uberon classes generalize species-specific ones, and connect to other ontologies via a variety of relations

OntoFox: a Web Server for MIREOTing Good things: Based on MIREOT principle Web-based data input and output Output OWL file can be directly imported in your ontology No programming needed Programmatically accessible

Improvements: Integration into ontology editing tools More customizable

http://ontofox.hegroup.org

Proposed model moving forward

Maintain series of ontologies at different taxonomic levels- euk, plant, metazoan, vertebrate, mollusc, arthropod,

insect, mammal, human, drosophila Each ontology imports/MIREOTs relevant subset of

ontology “above” it- this is recursive

Subtypes are only introduced as needed Work together on commonalities at appropriate

level above your ontology

zebrafish

caro / uberon/allcell tissue

metazoa

muscletissue

vertebrata

mesonephros

limb

arthropoda

antenna

teleost

weberian ossicle

mammalia

mammary gland

nervous system

mollusca

foot

cephalopod

tentacle

mantle

drosophila

neuron types XYZ

mushroom body

brachial lobe

NO pons

vertebravertebralcolumn

circulatory system

appendage

mesoderm

gut

tibia

gland

bone

skeletaltissue

parietalbone

fin

gonad

trachea

respiratoryairway

cross-ontologylink (sample)

amphibia

tibiafibula

larva

shellcuticle

skeleton

import

mouse human

Leveraging an integrated set of ontologies

Not all classification is useful

Be practical: Build ontologies for what you need and for what can be reused

About thirty years ago there was much talk that geologists ought only to observe and not theorise; and I well remember some one saying that at this rate a man might as well go into a gravel-pit and count the pebbles and describe the colours.C. Darwin

Ontologies can help reconcile annotation inconsistencies

Semantic Similarity of Phenotypes

"Linking Human Diseases to Animal Models Using Ontology-Based Phenotype Annotation." PLoS Biol 7(11): e1000247. doi:10.1371/journal.pbio.1000247 Washington NL, Haendel MA, Mungall CJ, Ashburner M, Westerfield M, Lewis SE

FMA+PATO MP ZFA+PATO FBbt+PATO

A

C

B

D EVertebrata

Ascidians

Arthropoda

Annelida

Mollusca

Echinodermata

tetrapod limbs

ampullae

tube feet

parapodia

Querying for genes in similar structures across species

Panganiban et al., PNAS, 1997

Distal-less orthologs participate in distal-proximal pattern formation and appendage morphogenesis

mouse limbsea urchin tube feet

ascidian ampulla polychaete parapodia

Anatomy ontologies in 2012 Identify key points of integration between ontologies Modularize based on domain or taxon

Import and reuse rather than cross-referencing or “aligning”

Let the reasoner help do the work Work together to distribute work

Reproduced with permission, Jason Freenyhttp://web.mac.com/moistproduction/flash/index.html

Anatomical evidence: what is it, and why do we care about it?

What is evidence?

Synaptolaemus cingulatusAMNH 91095

Draw prepared specimen

Drawing about anatomical entitym

aterial_processing

is_ou

tput

OBI: Interpreting Data-phenotypic assessment

Phenotype (character) annotation:S. Cingulatus: mesethmoid

narrowis_input

is_ou

tput

cleared and stained for cartilage and bone

OBI:processed specimen

is_in

put

OBI:imaging assay

OBI:Conclusion (textual entity)

OBI:Specimen

OBI:Image

Sidlauskas and Vari, Zoological Journal of the Linnean Society, 2008, 154, 70–210

Brian, 2008, maybe in Venezuela

ECO:000000XImaging assay evidence

Anatomical evidence is cumulative and synergistic

Synaptolaemus cingulatusAMNH 91095

mesethmoidnarrow

.

. OBI: Interpreting Data

Schizodon fasciatus INPA 21606

mesethmoidwide

..

is_input

is_ou

tput

Brian, 2008

Phylogeny construction using PAUP* 4.0 Beta 10

phylogeny

OBI:Conclusion

ECO:0000080phylogenetic evidence

Caenotropus maculosusUSNM 231545

mesethmoidnarrow

ECO:0000071morphological similarity evidence

The means to the end mattersSynaptolaemus cingulatus

AMNH 91095Mesethmoid

.

. OBI: Interpreting Data

Schizodon fasciatus INPA 21606

mesethmoidwide

..

is_input

is_ou

tput

Brian, 2008

Phylogeny construction using PAUP* 4.0 Beta 10

phylogeny

OBI:Conclusion

ECO:0000080phylogenetic evidence

Caenotropus maculosusUSNM 231545

mesethmoidnarrow

ECO:0000071sequence similarity evidence

So what should one do about evidence?

• Keep in mind that as you record your phenotype data, the means by which you obtained it can matter later one

• Others may want to use your data, and they too will care

• You may find that how you know what you know depends on the means to the end

• You can work with ECO and OBI to get the terms you need for your work

Acknowledgments Jonathan Bard Marcus Chibucos Wasila Dahdul Paula Mabee Chris Mungall David Osumi-Sutherland Alan Ruttenberg Erik Segerdell Carlo Torniai Matt Yoder Jie Zheng AND numerous others

Larson, October 1987