The document discusses the integration of genetic and phenotypic data through the use of ontologies, emphasizing the importance of structuring phenotype information for comparative biology. It highlights various ontological tools and databases that facilitate the analysis of gene expression, evolutionary relationships, and the application of standardized vocabularies for research. Key resources mentioned include the Gene Ontology, Uberon, and Phenoscape, which are pivotal for organizing biological knowledge across species.

1. GIGA2, Munich, March 2015
STRUCTURING
PHENOTYPE DATA:
Chris
Mungall
LBNL,
Berkeley
Gene
Ontology
Lessons from vertebrate
genomes

2. Web Apollo: http://genomearchitect.org

3. Desvignes, T., Pontarotti, P., & Bobe, J. (2010).
Nme gene family evolutionary history reveals pre-
metazoan origins and high conservation between
humans and the sea anemone, nematostella
vectensis. PLoS ONE, 5(11).
doi:10.1371/journal.pone.0015506
Genome
structures are
highly
amenable to
comparison

4.  Can we compute over the architecture of phenomes as we do
for genome architecture?
o What genes affect distal appendage length or shape?
o What are the genes expressed in the mouth during development?
o What structures develop using the same gene regulatory networks as
in bilaterian mouths?
 Current methods
o Text based search of literature and manually gather results
 Time consuming
 Hard to automate
COMPUTING OVER PHENOTYPES

5. Gene
Every phenotype ever to have existed
expressed
in mouth
Affects appendage length
regulates EMT …

6. PHENOTYPES: ENDLESS FORMS
PeytoianathorstiAmphipholissquamataPetromyzonmarinus
Bugula
Homosapiens
(withcleftpalate)
MystecetiAplysinaaerophoba
Gastrula(Metazoan)
mouth anusosculum
blastopore
cleft
lip and
palate

7. Gene “expressed
in mouth”
“affects appendage length”
“long tentacles”
“elongated arms”
FREE TEXT != STRUCTURED
“expressed
around oral
opening”
“expressed
in anterior
end of gut
tube”

8. ONTOLOGIES: STRUCTURING A DIVERSITY
OF PHENOTYPES
tentacle
tentacular
bud
circumoral
appendage
tentacular
club sucker
arm
develops
into
is a subtype of
Is part of
homologous
arm IV
https://github.com/obophenotype/cephalopod-ontology
mouth
surrounds

9. ONTOLOGIES FOR MOLECULAR
PHENOTYPES
tentacle
tentacular
bud
circumoral
appendage
tentacular
club sucker
arm
develops
into
is a subtype of
Is part of
homologous
arm IV
Scr Lox5 Antp
Expressed in
mouth
surrounds

10. GRAPH KNOWLEDGE QUERIES
tentacle
tentacular
bud
circumoral
appendage
tentacular
club sucker
arm
develops
into
is a subtype of
Is part of
homologous
arm IV
Scr Lox5 Antp
Expressed in
mouth
surrounds
“What genes
Are expressed in
structures that develop from
a tentacle bud, or homologs?”

11. ONTOLOGIES FOR TRAITS
tentacle
tentacular
bud
circumoral
appendage
tentacular
club sucker
arm
develops
into
is a subtype of
Is part of
homologous
arm IV
mouth
surrounds
shape length++
=
shape of
tentacular club
=
length of
arm IV

12.  Wild-type phenotypic function:
o The Gene Ontology
 Anatomy:
o Uberon anatomy ontology
APPLICATIONS OF ONTOLOGIES

13.  For curating the ‘wild type functional phenotypes’
 Genes for over 0.5 million species have associations to GO
terms
 >40,000 terms
o Molecular function
o Cellular component
o Biological Process
 Core and taxon-specific
 Uses include
o Gene set selection
o Term enrichment
THE GENE ONTOLOGY
Gene Ontology: tool for the unification of biology: Ashburner et al. Nature Genetics 25, 25 - 29 (2000)
http://geneontology.org

14.  Experimental
o Curated from literature
 Automated methods:
o Based on sequence similarity
 E.g. blast2go
o Based on protein features
 Interpro2GO
o Based on phylogenetic evidence
 Ensembl COMPARA
 Panther Families and PAINT
 Typically only applied for
conserved cellular biology
ASSIGNING GENE FUNCTION
Gaudet, P., et al. (2011). Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium.
Briefings in Bioinformatics, 12(5), 449–62. doi:10.1093/bib/bbr042
PAINT

15. EXTRACTING GENE LISTS AND
INTERPRETING TRANSCRIPTOMIC DATA
Wang, Z., Pascual-Anaya, J., Zadissa, A., Li, W., Niimura, Y., Huang,
Z., … Irie, N. (2013). The draft genomes of soft-shell turtle and
green sea turtle yield insights into the development and evolution
of the turtle-specific body plan. Nature Genetics, 45(6), 701–6.
doi:10.1038/ng.2615

16. BEYOND THE GO
Functional
Genomics: Gene
function
Transcriptomics:
Gene expression
Phenomics: Effects
of gene mutations
Gene Ontology
Anatomy and Stage
Ontology
Phenotype and Trait
Ontology
Links genes to
What they do
Links genes to
where they
are expressed
Links genes to
what happens
when they are
disrupted

17.  Core: 14,000 terms
o Bias towards vertebrate systems
 Composite-Metazoan edition: 42,000 terms
o Integrates cell types, developmental stages,
o Species-specific ontologies
 Uses
o Standard reference for animal anatomy
o Linking model organism databases
o Evolutionary systematics (Phenoscape)
o Comparative transcriptomics (Bgee)
o Standardized vocabulary for mammalian
sequencing consortia
o Cross-species phenotype matching (Monarch)
THE UBERON MULTI-SPECIES
COMPARATIVE ANATOMY ONTOLOGY
http://uberon.org
Mungall, C. J., Torniai, C., Gkoutos, G. V, Lewis, S. E., & Haendel, M. A. (2012). Uberon, an integrative multi-species
anatomy ontology. Genome Biology, 13(1), R5. doi:10.1186/gb-2012-13-1-r5

18. PHENOSCAPE: LINKING EVOLUTION TO
GENOMICS USING PHENOTYPE ONTOLOGIES
 Phenotypic knowledgebase
o Linking phenotypes to extant and extinct vertebrate taxa
o Integrate with model organism databases
 Extending Uberon to cover diversity of vertebrates
Haendel, MA, Balhoff JP, ..., Sereno, PC., Mungall, C.J (2014).
Unification of multi-species vertebrate anatomy ontologies for
comparative biology in Uberon. Journal of Biomedical Semantics,
5(1), 21. doi:10.1186/2041-1480-5-21

19. UBERON FOR COMPARATIVE GENE
EXPRESSION

20. EXAMPLE OF EXPRESSION DATA
Ensembl ID Gene Stage ID Stage Anatomy ID Anatomy Evidence
ENSMUSG
00000071424
Grid2 UBERON:00
00112
sexually
immature
UBERON:00
02979
Purkinje cell
layer of
cerebellar
cortex
high quality
ENSMUSG
00000071424
Grid2 UBERON:00
18241
prime adult UBERON:00
04720
cerebellar
vermis
high quality
Mus_musculus (‘simple’ expression file)
http://bgee.org/?page=download

21. EXAMPLE OF INFERRED EXPRESSION
DATA
Ensembl ID Gene Stage ID Stage Anatomy ID Anatomy Evidence
ENSMUSG
00000071424
Grid2 UBERON:0
000112
sexually
immature
UBERON:00
02979
Purkinje cell layer
of cerebellar cortex
high quality
ENSMUSG
00000071424
Grid2 UBERON:0
000112
sexually
immature
UBERON:00
02129
cerebellar cortex high quality
ENSMUSG
00000071424
Grid2 UBERON:0
000112
sexually
immature
UBERON:00
02979
cerebellum high quality
ENSMUSG
00000071424
Grid2 UBERON:0
000112
sexually
immature
UBERON:00
02028
hindbrain high quality
… …
ENSMUSG
00000071424
Grid2 UBERON:0
018241
prime
adult
UBERON:00
04720
cerebellar vermis high quality
ENSMUSG
00000071424
Grid2 UBERON:0
018241
prime
adult
UBERON:00
04720
cerebellum high quality
… …
Mus_musculus (‘complete’ expression file)
http://bgee.org/?page=download

22. CURATING A DATABASE OF HOMOLOGY
HYOPTHESES
https://github.com/BgeeDB/anatomical-similarity-annotations
gastrodermis
mouth
choanoderm
osculumhomologous
homologous
Leininger S, Adamski M, …
Adamska M
10.1038/ncomms4905Developmen
tal
Gene expression
evidence
Cnidaria Porifera

23. ONTOLOGIES FOR DATA
STANDARDIZATION IN SEQUENCING
CONSORTIA
Malladi, V. S., Erickson, D. T., Podduturi, N. R., Rowe, L. D., Chan, E. T., Davidson, J. M., … Hong, E. L. (2015). Ontology application and use at the
ENCODE DCC. Database : The Journal of Biological Databases and Curation, 2015, bav010–. doi:10.1093/database/bav010
Washington, N.L., Stinson, E.O., Perry, M.D. et al. (2011) The modENCODE Data Coordination Center: lessons in harvesting comprehensive
experimental details. Database, 2011, bar023
https://www.encodeproject.org/search/?type=biosample

24.  Monarch Initiative
o Large knowledgebase connecting genes, genotypes and diseases to
phenotypes
o Find novel linkages between human diseases to model systems
o http://monarchinitiative.org
 Driving use case
o Given a patient with a rare or unique spectrum of abnormal
phenotypes, determine the causative genomic variant(s)
DISEASES AND ABNORMAL PHENOTYPES

25. Standard Clinical
Exome
Testing Pipeline
Predicts causative variant based on information in genome of patient and
background genomic data

26. https://www.sanger.ac.uk/resources/databases/exomiser/query/exomiser2
Robinson, P., et al . (2013). Improved exome prioritization of
disease genes through cross species phenotype comparison.
Genome Research. doi:10.1101/gr.160325.113

27. http://monarchinitiative.org/analyze/phenotypes/
EXOMISER USES ONTOLOGY-BASED
PHENOTYPE MATCHING
cleft palate = cleft
(attribute)
palate
(structure)+

28. SOLVING UNDIAGNOSED
DISEASES
Behavioural/
Psychiatric
Abnormality
Thyroid
stimulating
hormone excess
Gait apraxia
Spasticity
increased
exploration in new
environment
increased
dopamine level
hyperactivity
hyperactivity
Behavioral
abnormality
Abnormality of
the endocrine
system
abnormal
locomotor
behavior
Abnormal
voluntary
movement
Patient
phenotypes Sh3kbp1 tm1Ivdi -/-
NIH Undiagnosed Disease Program, patient 2731

29.  Think about
o How your data will be re-used by others
o How what your doing will scale
 Provide structured metadata for experimental data
o Free text is not enough
o Use ontologies and standardized vocabularies where possible
 Failing to do so will cost you later!
o All major human and model organism omics consortia now enforce
this
 ENCODE, FANTOM, LINCS
o Also major phenotyping projects
 IMPC/KOMP2
LESSONS

30.  Providing metadata requires the right ontologies or
vocabularies in place
 Make phenotypic knowledge about your favorite system
structured and computable
o This seems daunting, where do I start…?
LESSONS

31.  Got transcriptome data?
o Bgee will curate it for you!
o Caveat: Your genome must be in Ensembl Genomes
o We are also interested in your homology hypotheses
 Got classic systematics data?
o Talk to me about using Phenoscape infrastructure
BGEE WILL CURATE YOUR
TRANSCRIPTOME DATA

32. Uberon Core
GOT ANATOMY EXPERTISE? CLAIM AN
INVERTEBRATE MODULE!
Thacker, R. W., Díaz, M. C., Kerner, A., Vignes-Lebbe, R., Segerdell, E.,
Haendel, M. a, & Mungall, C. J. (2014). The Porifera Ontology (PORO):
enhancing sponge systematics with an anatomy ontology. Journal of
Biomedical Semantics, 5(1), 39
Vertebrate
structures
Porifera
Ontology
Ctenophore
Ontology
Cephalopod
Ontology
http://phenotypercn.org
Eric Edsinger, CephSeq
https://github.com/obophenotype/cephalopod-ontology
https://github.com/obophenotype/ctenophore-ontology
https://github.com/obophenotype/porifera-ontology
https://github.com/obophenotype/uberon
Arthropod
Ontology

33. Noctua
 Curation using multiple
ontologies with a graph
model
oWeb-based, collaborative
oAdvanced GO curation
oPhenotype curation
 Beta available in
summer 2015
ohttp://noctua.berkeleybop.
org
CURATE GENE REGULATORY NETWORKS
AND PHENOTYPES

34.  Structured metadata is valuable
o Helps build the knowledge graph of invertebrate genomics
o Capture metadata up-front, not after the fact
o Use ontologies where possible
o Don’t repeat mistakes of projects that ignored this advice
 Invertebrate Ontologies at a nascent stage
o This is an opportunity! Get involved!
CONCLUSIONS

35.  Monarch
o Melissa A Haendel
o Nicole Washington
o Sebastian Kohler
o Harry Hochheiser
o Maryann Martone
o Suzanna Lewis
o Damian Smedley
o Peter Robinson
o William Bone
o Jeremy Nguyen-
Xuan
ACKNOWLEDGMENTS
 Uberon
o Frederic Bastian
o Ann Niknejad
o Marc Robinson-
Rechavi
o Todd Vision
o Jim Balhoff
o Paul Sereno
o Nizar Ibrahim
o Alex Dececchi
o Yvonne Bradford
o Terry Hayamizu
o Robert Druzinsky
 NSF Phenotype RCN
o Paula Mabee
o Suzanna Lewis
o Eva Huala
o Andy Deans
o Erik Segerdell
o Robert Thacker
o Eric Edsinger
o Matt Yoder
o Istvan Miko
o David Osumi-
Sutherland

37. Toward synthesizing our knowledge of morphology: using ontologies and machine reasoning to extract presence/absence
evolutionary phenotypes across studies. Dececchi TA et al. https://peerj.com/preprints/807/

38. FORWARD GENOMICS
http://bejerano.stanford.edu/phenotree/public/html/ Hiller et al. 2012 Cell Reports