Phenoscape: Connecting evolutionary

phenotypes to genes

Paula MabeeHilmar Lapp, Todd Vision, Monte

WesterfieldJim Balhoff, Wasila Dahdul, Peter

Midford

kb.phenoscape.org

Difficult to synthesize morphology across

studies

Difficult to relate to genetics & development

Cyprinus carpioCyprinus carpio

Pangio anguillarisPangio anguillaris

Nemacheilus fasciatusNemacheilus fasciatus

Catostomus commersoniCatostomus commersoni

Gyrinocheilus aymonieriGyrinocheilus aymonieri

Phenacogrammus interruptusPhenacogrammus interruptus

have their basis in changes in genetic control over development

Phenotypic differencesPhenotypic differences

Development understood from study of model organisms

Chen & Mayden, 2010

Zebrafish

ntla

•Model for vertebrate development

•Mutagenesis/gene knock-down

•Mutant phenotypes genes

•ZFIN resource

Problem:

photo J. Lundberg, ANSP 2002Pimelodus maculatus

•Species phenotypes genes at evolutionary scale

slc24a5 involved in pigmentation similarity between fish and humans (Lamason et al., 2005)

Zebrafish -- HumanConservation of gene sequence &

function and phenotype

Fig. 1, Washington et al., 2010

Translational medicine

Ameiurus nebulosus

http://tolweb.org/Trogloglanis/69910

Fig. 1, Washington et al., 2010

Catfish

Trogloglanispattersoni

gene?EQ: eye absent

Translational biodiversity?

Phenoscapekb.phenoscape.org

• 2007

•Goal: To prototype a curated, ontology-based evolutionary phenotype database that maps to genetic databases

•Devo-evo synthesis; candidate gene discovery

• Enable data-mining and discovery for broad scale evolutionary patterns

25 July 2009; ToL web

Ostariophysan fishes

User needs drove KB development:

•Search for candidate genes underlying evolutionary morphology

•Search for taxa with particular morphologies

•Aggregate morphological data across studies

Requirements (generic):

1.Ontologies

2.Curation

3.Database

1. Ontology: terms and relationships

is_apart_of

is_a

develops_from

part_ofreplacemenreplacemen

t bonet bone

basihyal basihyal bonebone

ventral ventral hyoid archhyoid arch

basihyal basihyal cartilagecartilage

pharyngeal pharyngeal arch arch

cartilagecartilage

is_abasihyal basihyal elementelement

Teleost Anatomy Ontology

2010. Dahdul, W. M., J. G. Lundberg, P. E. Midford, J. P. Balhoff, H. Lapp, T. J. Vision, M. A. Haendel, M. Westerfield, and P. M. Mabee. The Teleost Anatomy Ontology: Anatomical representation for the genomics age.

Systematic Biology (Cover art: Kyle Luckenbill)

Ontologies used by Phenoscape

Zebrafish Anatomy Zebrafish Anatomy OntologyOntology(2196 terms; 310 skeletal)(2196 terms; 310 skeletal)

Zebrafish Anatomy Zebrafish Anatomy OntologyOntology(2196 terms; 310 skeletal)(2196 terms; 310 skeletal)

Teleost Teleost Taxonomy Taxonomy OntologyOntology

(36,060 terms;(36,060 terms;38,000 synonyms)38,000 synonyms)

Teleost Teleost Taxonomy Taxonomy OntologyOntology

(36,060 terms;(36,060 terms;38,000 synonyms)38,000 synonyms)

Taxonomic Taxonomic Rank Rank

OntologyOntology(8->31 terms)(8->31 terms)

Taxonomic Taxonomic Rank Rank

OntologyOntology(8->31 terms)(8->31 terms)

Teleost Anatomy Teleost Anatomy OntologyOntology

(2371 terms; 618 skeletal)(2371 terms; 618 skeletal)

Teleost Anatomy Teleost Anatomy OntologyOntology

(2371 terms; 618 skeletal)(2371 terms; 618 skeletal)

Phenotype and Phenotype and Trait Ontology Trait Ontology

(PATO)(PATO)(1,075 terms)(1,075 terms)

Spatial OntologySpatial Ontology(106 terms)(106 terms)

6 Jan 2009

EvidenceEvidenceCodeCode

OntologyOntology

•Curated 4,732 characters in 2,474 species from 52 papers

•501,862 taxon phenotype annotations

•From ZFIN: 21,829 phenotype annotations about 3,893 genes

•Curated 4,732 characters in 2,474 species from 52 papers

•501,862 taxon phenotype annotations

•From ZFIN: 21,829 phenotype annotations about 3,893 genes

2. CurationDahdul et al., 2010 PLoS ONE

2. Students: Manual entry of

free text character descriptions,

matrix, taxon list, specimens and

museum numbers using Phenex

2. Students: Manual entry of

free text character descriptions,

matrix, taxon list, specimens and

museum numbers using Phenex

3. Character annotation by

experts: Entry of phenotypes using

Phenex

3. Character annotation by

experts: Entry of phenotypes using

Phenex

Curators:Wasila DahdulMiles CoburnJeff EngemenTerry GrandeEric HiltonJohn LundbergPaula MabeeRichard MaydenMark Sabaj Pérez

~ 5 person years~ 5 person years

1. Students: gather publications (scan

hard copies, produce OCR PDFs)

1. Students: gather publications (scan

hard copies, produce OCR PDFs)

4. Phenoscape Knowledgebase: OBD,

data services, web application

4. Phenoscape Knowledgebase: OBD,

data services, web application

5K Karacter ChallengeOntology boot camp,

NESCent 2005Phenoscape Data Roundup

photo: NESCent

photo: Monte Westerfield

Buffalo Roundup, SD

Entity-Quality Model for Taxon Phenotypes

ethmoid cartilageethmoid cartilage

ethmoid plate formethmoid plate form

Entity (TAO)

roundedrounded

Character

roundround

Quality (PATO)

State}Phenotype

Taxon phenotype annotations

round that

inheres_in some

ethmoid cartilage

round that

inheres_in some

ethmoid cartilage

exhibits some

Taxon ontology term

Anatomy ontology term

Phenotypic Quality ontology term

Links a quality to the entity that is its

bearer

Brachyplatystoma capapretum

Brachyplatystoma capapretum

split that

inheres_in some

ethmoid cartilage

split that

inheres_in some

ethmoid cartilage

influences some

Gene phenotype annotations

Import from ZFIN data in EQ format

tfap2ats213/ts213

tfap2ats213/ts213

Brachyplatystoma capapretum

Brachyplatystoma capapretum

round that

inheres_in some

ethmoid cartilage

round that

inheres_in some

ethmoid cartilage

exhibits some

tfap2ats213/ts213

tfap2ats213/ts213

split that

inheres_in some

ethmoid cartilage

split that

inheres_in some

ethmoid cartilage

influences some

roundround

splitsplit

ethmoid cartilage

ethmoid cartilage

Brachyplatystoma

Brachyplatystoma

tfap2atfap2a

is_a

variant_of inheres_

in

inheres_in

is_a

is_a

shapeshape

chondrocranium cartilage

chondrocranium cartilage

olfactory region

olfactory region

PimelodidaePimelodidae

sequence-specific DNA binding

transcription factor activity

sequence-specific DNA binding

transcription factor activity

is_a

has_function is_a part_of

is_ais_a

Knowledgebase architecture

Phenoscape Knowledgebase

501,862 taxon phenotypes

21,829 gene phenotypes for

3,893 genes

kb.phenoscape.org

Interativeuser

testing ofinterface

KB inferred candidate genes

Phenotypic profile for Siluriformes

includes:Scales absent; Basihyal absent

Phenotypic profile for Siluriformes

includes:Scales absent; Basihyal absent

30% <1%

position

composition

25% 20% 15% 10%

count

shape structuresize

PATO qualities used in phenotypes

Siluriform synapomorphies:

Ictalurus punctatus

Copyright © Jean Ricardo Simões Vitule, All Rights Reserved

Scales absent Basihyal absent

Ictalurus punctatus

Photo: Richard Edmunds

Zebrafish mutant phenotypes

Harris et al., 2007

eda: scale loss brpf1: basihyal loss

Laue et al., 2008

In silico prediction of candidate genes

Ictalurus punctatus

Copyright © Jean Ricardo Simões Vitule, All Rights Reserved

Scales absent: eda? Basihyal absent: brpf1?

Ictalurus punctatus

Photo: Richard Edmunds

Wet lab test (Richard Edmunds)

Lack of eda expression in the epidermis supports Phenoscape KB

hypothesis

Ictalurus punctatus

eda

Wet lab test (Richard Edmunds)Ictalurus punctatus

78 hpf 86 hpfLack of brpf1 expression in the basihyal supports Phenoscape KB

hypothesis

E.g., distribution of all characters across

anatomical systems in taxa

25 July 2008

E.g., distribution of skeletal characters in broad regions

across taxa

Image from Sabaj-Perez

25 July 2008

Summary•Powerful queries not previously

possible for evolutionary phenotype data

•Meaningful integration with model organism phenotypic and genetic data

•Makes data accessible for broad group of researchers and creates opportunities for new and synthetic research

Semantic framework and reasoning tools provide:

Phenoscape as a resource

•Ontologies (anatomy, quality, taxon) + EQ data for any taxon

•Reasoning across EQ data types, uniting multiple studies, genes, etc.

•Your data?

AcknowledgmentsPhenoscape Personnel & PIs:P. Mabee,M. Westerfield, T. Vision,H. Lapp,C. Kothari,W. Dahdul,P. Midford,R. EdmundsPhenoscape curators & workshop participants

Berkeley Bioinformatics & Ontologies Project (BBOP):C.Mungall, S.LewisNational Evolutionary Synthesis Center (NESCent)NSF (DBI 0641025)