The document discusses the integration of diverse phenotypic data for evolutionary biology, detailing a collaborative project aimed at creating a machine-interpretable database of evolutionary phenotypes. It emphasizes the challenges of computing and encoding phenotypic information and presents various methodologies for data mining, hypothesis generation, and visualizing phenotype variation. The initiative aims to foster synthesis between developmental and evolutionary biology by linking evolutionary characters to genomic data and facilitating research on phenotype changes across species.

1. Bringing reason to
phenotype diversity,
character change, and
common descent
Hilmar Lapp
National Evolutionary Synthesis Center (NESCent)
NCBO Webinar, Nov 17, 2010

2. Regier et al (2010
Parfrey et al (2010, Parfrey & Katz
Life has
evolved a
stunning
diversity of
phenotypes
Images: Web Tree of Life (http://tolweb.org)

3. Large body of evolutionary
phenotype documentation

4. Chen & Mayden (2010)
Phenotype
Mabee (2000) changes inform
phylogenetic
reconstruction
from: Understanding Evolution Sereno (1999)

5. As complex, free text phenotypes
are resistant to computing
(Lundberg and Akama 2005)

6. Finding similar information
in free-text is difficult
“lacrymal bone...flat’’ Mayden 1989
Grande and Poyato-
“lacrimal...small, flat”
Ariza 1999
“lacrimal...triangular’’ Royero 1999
“first infraorbital (lachrimal)
Kailola 2004
shape...flattened”
“fourth infraorbital...anterior and
Zanata and Vari 2005
posterior margins...in parallel”

7. Computing
example:
Search by
Similarity
Fig. 3, Washington et al (2009)
Fig. 1, Washington et al (2009)

8. Computing
example:
Search by
Similarity
Fig. 3, Washington et al (2009)
Trogloglanis pattersoni - a blind catfish
http://tolweb.org/Trogloglanis/69910
Fig. 1, Washington et al (2009)

9. Integrating across studies?
Fig. 7, Sereno (2009)
Fig. 6, Sereno (2009)

10. Computing over
comparative morphology?
Cyprinus carpio Pangio anguillaris Nemacheilus fasciatus
Catostomus commersoni Gyrinocheilus aymonieri Phenacogrammus interruptus

11. Knowledge mining &
hypothesis generation
Model Organism Non-model organisms
Mutagenesis Mutation, selection, drift, gene flow
Mutant or missing protein at Altered expression or
specific developmental stage function of protein
Phenotype change(s) Phenotype changes between
to wildtype evolutionary lineages
middle nuchal plate predorsal
spinelet spine
anterior
nuchal plate
Order Siluriformes
Laue et al (2008) Pimelodus maculatus 2 cm abdominal Order Characiformes
scutes Catoprion mento

12. Phenoscape
• Collaboration between P. Mabee (PI, U. South
Dakota), M. Westerfield (ZFIN), and Todd Vision
(UNC, NESCent)
• Aim: Foster devo-evo synthesis by
• Prototyping a database of curated, machine-
interpretable evolutionary phenotypes.
• Integrating these with mutant phenotypes from
model organisms.
• Enabling data-mining and discovery for candidate
genes of evolutionary phenotype transitions.
• Informatics for the project is developed and hosted
at NESCent

13. Entity-Quality Model for
Evolutionary Phenotypes
Character State
supraorbital bone shape bent
Entity (TAO) Quality (PATO)
supraorbital bone bent

14. Entity-Quality Model for
Evolutionary Phenotypes
Character State
supraorbital bone shape bent
Entity (TAO) Quality (PATO)
supraorbital bone bent

15. Entity-Quality Model for
Evolutionary Phenotypes
Character State
supraorbital bone shape bent
Entity (TAO) Quality (PATO)
}supraorbital bone bent
Phenotype

16. Phenotype Assertion
Links a quality to the
entity that is its bearer
Links a taxon to a Phenotypic Quality
phenotype ontology term
bent
Brycinus exhibits inheres_in
brevis some supraorbital
bone
Taxon Anatomy
ontology term ontology term

17. Phenotype Assertion
Links a quality to the
entity that is its bearer
Links a taxon to a Phenotypic Quality
phenotype ontology term
bent
Brycinus exhibits inheres_in
brevis some supraorbital
bone
Taxon Anatomy
ontology term ontology term
Evidence
Specimen Publication
Code

18. Ontology development
Ontologies for
• Teleost Anatomy
• Teleost Taxonomy
Dahdul et al (2009)
• Phenotypic
Quality (PATO)
Cover art: K. Luckenbill

19. Curation
Dahdul et al., 2010 PLoS ONE
2. Students:
3. Character
Manual entry of free
annotation by experts:
text character
Entry of phenotypes
descriptions, matrix,
and homology
taxon list, specimens
assertions using
and museum numbers
Phenex
using Phenex
~ 5 person years
Curators:
Wasila Dahdul
Miles Coburn
Jeff Engemen
Terry Grande
1. Students: Eric Hilton
gather publications John Lundberg 4. Consistency
(scan hard copies, Paula Mabee checks, upload of
produce OCR PDFs) Richard Mayden data to public view of
Mark Sabaj Pérez Phenoscape KB

21. • Curated 4,208 characters in 2,310 species
from 51 papers
• 333,987 evolutionary phenotype assertions
• 11,267 phenotype statements about 2,953
genes

22. Phenoscape Knowledgebase

27. Full workflow:
free-text → EQ → integrated KB
legacy free-text EQ = body
character data lacks all Taxon Gene Anatomical Entity Quality
parts of type anatomical has number
Teleostei eda
scale structure of
is_a is_a is_a
is_a
Siluriformes is_a body scale
lacks all
Kailola (2004)
inheres_in towards parts of type
Gasterosteiformes inheres_in towards
is_a is_a is_a
is_a variant_of inheres_in towards
is_a
© Jean Ricardo Simões Vitule has fewer
body lacks all parts of type
Ictalurus punctatus exhibits
mutant phenotype EQ = body parts of type scale
Here, we describe the phenotypic and
has fewer is_a
molecular characterization of a set of parts of type body lacks all
mutants showing loss of adult structures of Apeltes quadracus exhibits
the dermal skeleton, such as the rays of the scale parts of type scale
fins and the scales, as well as the
pharyngeal teeth. The mutations represent
adult-viable, loss of function alleles in the body has fewer
ectodysplasin (eda) and ectodysplasin edadt3S243X/+ influences
parts of type scale
receptor (edar) genes.
Harris et al. (2008)

28. System architecture
Knowledgebase User Inteface External web sites
Web Application for Exploration & Mining and client
(Ruby on Rails, JavaScript) applications
Knowledgebase Data Services API (REST)
OBD Programming API
OBD Reasoner
(Java)
Teleost Taxonomy
Ontology (TTO)
Knowledgebase (OBD)
(PostgreSQL)
Phenotypic
Anatomy Quality Ontology
Ontologies (PATO)
(ZFA, TAO)
Genes & genotypes Homology assertions
Mutant EQ phenotypes Evolutionary EQ Phenotypes NeXML
OBO Library
from Zebrafish Model (through annotation)
Organism Database
Phenex Skeletal Character Data
(Evolutionary EQ (from phylogenetic
annotation) treatments in literature)

29. KB is based on OBD
(Ontology-Based Database)
(C. Mungall, LBL)

30. PATO:quality Measurement ZFIN:Publication
ECO:evidence curator(s) -value/max/min uid = ZFIN ID
-unit
OBO_REL:is_a
OBO_REL:posited_by
has_measurement
has_evidence dc:creator
TAO:taxon PHENO:exhibits Phenotype OBO_REL:influences
(class expression) Genotype
OBO_REL:towards
OBO_REL:inheres_in
OBO_REL:variant_of
PHENO:asserted_for_otu TAO:entity
OBO_REL:posited_by
PHENO:has_taxon
OBO_REL:posited_by TAO:entity Gene
CDAO:TU
name = Publication Taxon CDAO:CharacterStateDomain
CDAO:CharacterStateDatum CDAO:has_State
name = state text
dwc:individualID
PHENO:has_comment
PHENO:has_comment
comments CDAO:has_TU dwc:collectionID COLLECTION
(literal text) Specimen
dwc:catalogID comment
CDAO:has_Datum (literal text)
catalog number
(literal text)
CDAO:CharacterStateDataMatrix
CDAO:has_Character
CDAO:Character
PHENO:has_publication name = character text
PHENO:has_comment
PHENO:Publication PHENO:has_comment
-dc:abstract publication notes
-dc:bibliographicCitation (literal text) comment
-dc:date (literal text)

31. Phenoscape OBD reasoner
• All OBD built-in rules:
• is_transitive(R), X R Y, Y R Z → X R Z
• is_reflexive(R) → X R X
• X is_a Y, Y R some Z → X R some Z
• Y is_a Z, X R some Y → X R some Z
• X R Y, Y S Z, transitive_over(R,S) → X
R Z
• X R1 Y, Y R2 Z,
holds_over_chain(R,R1,R2) → X R Z
• Additional Phenoscape rule:
• T exhibits P, T is_a T’ → T’ exhibits P
• Consistent with OWL due to instance
quantification

32. Major taxonomic groups have
similar distribution of entities
among phenotypes

33. Substantial overlap between
model organism and
evolutionary phenotypes
hematopoie7c system •4,217 zebrafish phenotypes
reproduc7ve system •3,405 evolutionary characters
musculature system
liver and biliary system
respiratory system
renal system
endocrine system Evolu7onary characters
Zebrafish phenotypes
immune system
diges7ve system
cardiovascular system
skeletal system
sensory system
nervous system
0 500 1000 1500 2000 2500

34. Hypothesis generation:
Genetic basis for scale loss in
Siluriformes
Mutation of eda gene Ictalurus punctatus:
in Danio:
Harris et al., 2007
Copyright
©
Jean
Ricardo
Simões
Vitule,
All
Rights
Reserved

35. Hypothesis generation:
Genetic basis for absence of the
basihyal bone in Siluriformes
Mutation of brpf1 gene Ictalurus punctatus:
in Danio:
Laue et al (2008)

36. Making PATO usable for evolutionary data
Attribute Example Qualities
Color black, colorless Attribute Example Qualities
Composition cartilaginous, ossified Relational Spatial anterior to, lateral to
Count present, absent Relational Structural fused with, overlap with, separated from
Position horizontal, vertical Shape concave, interdigitated, lobed, triangular
Quality open, closed, flexible Size increased length, decreased length
Relational Shape protruding into Texture wrinkled, smooth

37. Getting PATO right is a challenge
• PATO is “single-inheritance” - what is the right
axis of classification?
• relational shape vs monadic shape
• relational spatial vs position
• shape and size vs natural language
”Interopercle shape: expanded posteroventrally”
• Different ways to observe or generate a
phenotypic quality
• Color as color hue (radiation quality) or
pigmentation (structural quality)
• Relative sizes don’t have a universal reference
• Negation (“not round”, “unelongated”): means
complement under attribute ‘(shape and not(round))’

38. Mapping EQs back to
characters is a challenge
• Properties of “good” phylogenetic characters:
• Exclusivity of states
• Distinguishability of states
• Independence of characters
• Finding exclusive states requires incompatible
phenotypes. How to determine incompatibility?
• Two phenotypes are incompatible iff they
cannot both inhere in the same specimen.
• Two qualities are incompatible iff an entity
cannot bear both.

39. Which EQs and qualities
are incompatible?
• Incompatible Qs • Compatible Qs
• present vs. absent • present vs. any
• triangular vs. other quality
round (except absent)
• absent vs. any • serrated vs. round
other quality • some colors
• Incompatible EQs
• (Q inheres_in bone
E) vs (cartilage E
absent)

40. Detecting phenotype
change and variation
Hemiodus argenteus {shape:bent inheres_in supraorbital bone,
count:absent inheres_in upper pharyngeal
5 tooth}
{shape:bent inheres_in supraorbital bone,
Hemiodus shape:straight inheres_in supraorbital bone,
count:absent inheres_in upper pharyngeal 5 tooth,
count:present inheres_in upper pharyngeal 5 tooth}
{shape:straight inheres_in supraorbital
Hemiodus unimaculatus bone,
count:present inheres_in upper
pharyngeal 5 tooth}
{Change in: shape inheres_in supraorbital bone,
Change in: count inheres_in upper pharyngeal 5 tooth}

41. Visualizing phenotype profiles on a tree
Phenotypic profile: Phenotypic profile tree
Taxon color indicates the greatest level of match of specified phenotype(s)
Phenotypes
found within a species in the clade.
dorsal fin absent X Phenotype match
including parts
adipose fin absent X 100%
including parts
75%
opercle triangular X 50%
including parts
<50%
Include inferred phenotypes
Query taxa with these phenotypes.

42. Navigating phenotype variation on a tree
entity term: basihyal bone
Taxonomic distribution of for basihyal bone
Limit tree to Cypriniformes X
or Sets of taxa with matching
Phenotype Profiles
Show taxa without phenotype data
Show taxa with unspecified shape phenotypes
Cyprinidae
Osariophysii Cypriniformes Balitoridae
Phenotype Gyrinocheilidae
Phenotype Taxa
Profiles Cobitidae
triangular 1 1 Vaillantellidae
Y-shaped 1 1 Botiidae
Catostomidae
shape 8 3
Psilorhynchidae

43. Entity 1 Taxon 1 Relationship Entity 2 Taxon 2 Evidence Reference(s)
(Fink and Fink,
1981; Rosen and
scaphium Otophysi homologous_to neural arch 1 Teleostei IDS, IMS, IPS
Reasoning
Greenwood,
1970)
neural arch 2 (Rosen and
intercalarium Otophysi homologous_to (ventral Teleostei IDS, IMS, IPS Greenwood,
intercalarium Otophysi
portion)
homologous_to neural arch 2 Teleostei NAS
1970)
(Fink and Fink,
1981)
over
homology
intercalarium Otophysi homologous_to neural arch 2 Teleostei IMS (Hora, 1922)
intercalarium Otophysi homologous_to rib of vertebra 2 Teleostei TAS (Hora 1922)
(Fink and Fink,
parapophysis + 1981; Rosen and
tripus Otophysi homologous_to Teleostei IDS, IMS, IPS
rib of vertebra 3 Greenwood,
1970)
image by Kyle Luckenbill, ANSP

44. Formalizing homology
relationships
• Formal pattern is ternary:
E1 in_taxon T1 homologous_to E2 in_taxon T2 as E3 in_taxon T3
• Classifying homology relationships
• 1-1 homology (phylogenetic homology)
• serial homology
• A iso_homologous_to B as C
all A derived_by_descent_from some
(C and has_derived_by_descendent some B)
and
all B derived_by_descent_from some
(C and has_derived_by_descendent some A)
• shares_ancestor_with as a relation chain:
derived_by_descent_from o has_derived_by_descendent

45. Option 1: Asserting homology
at higher-level taxa

46. Option 2: Asserting homology
at species level

47. Validation through standard
OWL-DL reasoning

49. Opening descriptive biological data to
computing can enable new science
Taxonomy, Conservation
Species ID Biology
Biodiversity
(Specimens,
Occurrence
records)
Descriptive biology Ecology
- Phenotypes
- Traits
- Function
- Behavior
- Habitat
- Life Cycle
- Reproduction
Physiology - Conservation Threats Genetics
Genomics,
Genetic
Gene
variation
expression

50. Acknowledgements
• Phenoscape • Berkeley Bioinformatics
Personnel & PIs: & Ontologies Project
P. Mabee, (BBOP):
M. Westerfield, C.Mungall, S.Lewis
T. Vision,
J. Balhoff, • National Evolutionary
C. Kothari, Synthesis Center
W. Dahdul, (NESCent)
P. Midford
• NSF (DBI 0641025)
• Phenoscape curators &
workshop participants