From baleen to cleft palate:
an ontological exploration of
evolution and disease
Melissa Haendel
July 11 , 2014
17th Annua...
Baleen whales
The baleen whales are characterized by having baleen plates for filtering food
from water, rather than teeth...
Fin whale fetus showing tooth buds in
upper jaw
Deméré TA et al. 2008© 2008 Society of Systematic Biologists
Changes in enamel genes during
evolution of teeth within Cetacea
Meredith R W et al. Proc. R. Soc. B 2011;278:993-1002©201...
Cleft palate
Cranial neural crest contributes to
the jaw and palate
Dougherty et al. 2013 Development 140, 76-81
sox10:kaede transgenic...
Vertebrata
Ascidians
Arthropoda
Annelida
Mollusca
Echinodermata
tetrapod limbs
ampullae
tube feet
parapodia
We want to und...
Anatomy ontologies built for one
species will not work for others
http://fme.biostr.washington.edu:8080/FME/index.html
htt...
lung
lung
lobular organ
parenchymatous
organ
solid organ
pleural sac
thoracic
cavity organ
thoracic
cavity
abnormal lung
m...
lung
lung
lobular organ
parenchymatous
organ
solid organ
pleural sac
thoracic
cavity organ
thoracic
cavity
abnormal lung
m...
Why not just map ontology terms?
Class A Class B Mapped? Useful?
FMA: extensor
retinaculum of wrist
MouseAnatomy: retina Y...
Fossils, the ultimate silo
 Modern diversity only a fraction of
evolutionary diversity
 Missing evolutionary transitions...
Avoiding Silo-ization
Use ontologies that are:
 open
 documented
 reusable
 interoperable
 built according to shared ...
Long ago in the world of anatomies
CARO
FBbt
Drosophila
MA
Adult
mouse
EMAP
embryonic
mouse
FMA
(mostly)
adult
human
EHDAA...
And then came Uberon, created to
bridge model organism anatomies
CARO
FBbt
Drosophila
MA
Adult
mouse
EMAP
embryonic
mouse
...
And over time…
… additional multi-species ontologies evolved
CARO
FBbt
Drosophila
MA
Adult
mouse
EMAP
embryonic
mouse
FMA
...
CARO
FBbt
Drosophila
MA
Adult
mouse
EMAP
embryonic
mouse
FMA
(mostly)
adult
human
EHDAA2
embryonic
human
ZFA
zebrafish
XAO...
And there was asynchrony in the
(anatomical) universe
Cross referenced content
pre-merge
The new Uberon
 Contents:
– Over 11,000 classes (terms), 2500+ added in merge.
– Many anatomical properties, including su...
What can you do with the new
uberon?
Modified from Ahn and Ho 2008
 Reason across anatomical variation in extinct and ext...
B6.Cg-Alms1foz/fox/J
increased weight,
adipose tissue volume,
glucose homeostasis altered
ALSM1(NM_015120.4)
[c.10775delC]...
Representing phenotypes
Post-composed “EQ”
phenotype description
Entity (Anatomy, Spatial, Gene Ontology)
BSPO: anterior region part_of ZFA:head
Z...
Human Phenotype Ontology
Human Phenotype
Ontology used to
annotate:
• Patients
• Disorders
• Genotypes
• Genes
• Sequence ...
Mammalian Phenotype Ontology
Smith et al. (2005). The Mammalian Phenotype Ontology as a
tool for annotating, analyzing and...
Phenotype representation requires
more than “phenotype ontologies”
glucose
metabolism
(GO:0006006
)
Gene/protein
function
...
The Biological Spatial Ontology
 Evolutionary changes in spatial
arrangement
 Different standards in different
communiti...
The Biological Spatial Ontology
Non-perpendicular anatomical axes
Cellular anatomical directions
Dahdul et al. Nose to tai...
Spatial ontology content
anterior-posterioraxis
anatomicalaxis
is_a
anteriorside
starts_axis
posteriorside
finishes_axis
a...
Putting it all together
monarchinitiative.org
Uberpheno – building a cross-
species semantic framework
Köhler et al. (2014) Construction and accessibility of a cross-sp...
Uberpheno construction
Uberpheno construction
Uberpheno construction
Uberpheno construction
Facial features are so specific as to
enable image based diagnostics
iphone App
=> Uses HPO for annotations
What genotype-phenotype data do we
have?
GWAS
+
ClinVar
+
OMIM
Human genes have poor phenotype coverage
What else can we l...
Human genes have poor phenotype coverage
What else can we leverage? …animal data
Orthology via PANTHER v9
What genotype-ph...
Combined, human and model phenotypes can
be linked to >75% human genes.
Orthology via PANTHER v9
What genotype-phenotype d...
Monarch phenotype data
Also in the system: Rat; IMPC; GO annotations; Coriell cell lines; OMIA; MPD; Yeast; CTD;
GWAS; Pan...
r
Long hallux
Midface
retrusion
Arthrogryposis
multiplex
congenita
Bowing of the
long bones
Cleft palate
Exaggerated
Cupid...
https://www.sanger.ac.uk/resources/databases/exomiser/query/exomiser2
Undiagnosed patient 2731
Behavioural/
Psychiatric
Abnormality
Thyroid
stimulating
hormone excess
Gait apraxia
Spasticity
i...
What if there aren’t any similar
diseases or other organisms?
YARS
MARS
IARSIL41L
AARSIARS2
Abnormal
stereopsis
Choreoathe...
Forward Genomics
http://bejerano.stanford.edu/phenotree/public/html/ Hiller et al. 2012 Cell Reports
Connecting baleen and palates
Conclusions
 Uberon integrates anatomy across human, model, and
non-model organisms
 Anatomy and phenotypes can be repre...
Acknowledgments
NIH-UDP
William Bone
Murat Sincan
Amanda Links
Neal Boerkoel
Cyndi Tifft
Bill Gahl
OHSU
Nicole Vasilesky
S...
From baleen to cleft palate: an ontological exploration of evolution and disease
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From baleen to cleft palate: an ontological exploration of evolution and disease

  1. 1. From baleen to cleft palate: an ontological exploration of evolution and disease Melissa Haendel July 11 , 2014 17th Annual Bio-Ontologies SIG
  2. 2. Baleen whales The baleen whales are characterized by having baleen plates for filtering food from water, rather than teeth like in the toothed whales
  3. 3. Fin whale fetus showing tooth buds in upper jaw Deméré TA et al. 2008© 2008 Society of Systematic Biologists
  4. 4. Changes in enamel genes during evolution of teeth within Cetacea Meredith R W et al. Proc. R. Soc. B 2011;278:993-1002©2011 by The Royal Society
  5. 5. Cleft palate
  6. 6. Cranial neural crest contributes to the jaw and palate Dougherty et al. 2013 Development 140, 76-81 sox10:kaede transgenic zebrafish
  7. 7. Vertebrata Ascidians Arthropoda Annelida Mollusca Echinodermata tetrapod limbs ampullae tube feet parapodia We want to understand gene function across taxa
  8. 8. Anatomy 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
  9. 9. lung lung lobular organ parenchymatous organ solid organ pleural sac thoracic cavity organ thoracic cavity abnormal lung morphology abnormal respiratory system morphology MP MA FMA abnormal pulmonary acinus morphology abnormal pulmonary alveolus morphology lung alveolus organ system respiratory system Lower respiratory tract alveolar sac pulmonary acinus organ system respiratory system EHDAA2 lung lung bud respiratory primordium pharyngeal region develops_from part_of is_a (SubClassOf) surrounded_by So we build species-specific ontologies
  10. 10. lung lung lobular organ parenchymatous organ solid organ pleural sac thoracic cavity organ thoracic cavity abnormal lung morphology abnormal respiratory system morphology MPO MA FMA abnormal pulmonary acinus morphology abnormal pulmonary alveolus morphology lung alveolus organ system respiratory system Lower respiratory tract alveolar sac pulmonary acinus organ system respiratory system EHDAA2 lung lung bud respiratory primordium pharyngeal region But this results in silos develops_from part_of is_a (SubClassOf) surrounded_by
  11. 11. Why not just map ontology terms? Class A Class B Mapped? Useful? FMA: extensor retinaculum of wrist MouseAnatomy: retina Yes No Vivo: legal decision Cognitive Atlas: decision Yes No PlantOntology: Pith MouseAnatomy: medulla Yes No TaxRank: domain NCI: protein domain Yes No ZfishAnat: hypophysis MouseAnatomy: pituitary No Yes TAO:fossa AdverseReactions: depression Yes No FMA: colon GAZ: Colón, Panama Yes No Quality: male Chebi: maleate 2(-) Yes No String matching for mapping can lead to spurious results and semantics of mappings and provenance are not always clear
  12. 12. Fossils, the ultimate silo  Modern diversity only a fraction of evolutionary diversity  Missing evolutionary transitions e.g. fin to limb  Extant ontologies not always compatible with fossil data  Different data sources and resolution between extinct and extant Shubin et al. 2006
  13. 13. Avoiding Silo-ization Use ontologies that are:  open  documented  reusable  interoperable  built according to shared principles  reuse core relations and patterns Problem: How do we re-use in the presence of variability?
  14. 14. Long ago in the world of anatomies CARO FBbt Drosophila MA Adult mouse EMAP embryonic mouse FMA (mostly) adult human EHDAA2 embryonic human ZFA zebrafish XAO Xenopus An anatomical reference ontology was built to help standardize species-specific ontologies
  15. 15. And then came Uberon, created to bridge model organism anatomies CARO FBbt Drosophila MA Adult mouse EMAP embryonic mouse FMA (mostly) adult human EHDAA2 embryonic human ZFA zebrafish XAO Xenopus UBERON
  16. 16. And over time… … additional multi-species ontologies evolved CARO FBbt Drosophila MA Adult mouse EMAP embryonic mouse FMA (mostly) adult human EHDAA2 embryonic human ZFA zebrafish XAO Xenopus TAO Teleost HAO Hymenoptera Arthropod VSAO Vertebrate Skeletal AAO Amphibian UBERON vHOG Vertebrate Homologous Organs Group
  17. 17. CARO FBbt Drosophila MA Adult mouse EMAP embryonic mouse FMA (mostly) adult human EHDAA2 embryonic human ZFA zebrafish XAO Xenopus TAO Teleost HAO Hymenoptera Arthropod VSAO Vertebrate Skeletal AAO Amphibian UBERON vHOG Vertebrate Homologous Organs Group But… …they had a hard time maintaining relationships to one another
  18. 18. And there was asynchrony in the (anatomical) universe
  19. 19. Cross referenced content pre-merge
  20. 20. The new Uberon  Contents: – Over 11,000 classes (terms), 2500+ added in merge. – Many anatomical properties, including subclass, part-of and develops-from  Scope: metazoa (animals) – Current focus is chordates – Includes teleost, amniote, and amphibian specific classes  Uberon classes are generic / species neutral – ‘mammary gland’: you can use this class for any mammal! – ‘lung’: you can use this class for any vertebrate (that has lungs) http://purl.obolibrary.org/obo/uberon/ext.obo http://purl.obolibrary.org/obo/uberon/ext.owl uberon.org
  21. 21. What can you do with the new uberon? Modified from Ahn and Ho 2008  Reason across anatomical variation in extinct and extant taxa  Query for candidate genes relevant to morphological evolution  Use morphological diversity to investigate human malformations kb.phenoscape.orgmonarchinitiative.org Jim Balhoff talk tomorrow: Presence-absence reasoning for evolutionary phenotypes
  22. 22. B6.Cg-Alms1foz/fox/J increased weight, adipose tissue volume, glucose homeostasis altered ALSM1(NM_015120.4) [c.10775delC] + [-] GENOTYPE PHENOTYPE obesity, diabetes mellitus, insulin resistance increased food intake, hyperglycemia, insulin resistance kcnj11c14/c14; insrt143/+(AB) Models recapitulate various phenotypic aspects of disease ?
  23. 23. Representing phenotypes
  24. 24. Post-composed “EQ” phenotype description Entity (Anatomy, Spatial, Gene Ontology) BSPO: anterior region part_of ZFA:head ZFA:heart ZFA:ventral mandibular arch GO:swim bladder inflation Quality (PATO) Small size Edematous Thick Arrested
  25. 25. Human Phenotype Ontology Human Phenotype Ontology used to annotate: • Patients • Disorders • Genotypes • Genes • Sequence variants In human Reduced pancreatic beta cells Abnormality of pancreatic islet cells Abnormality of endocrine pancreas physiology Pancreatic islet cell adenoma Pancreatic islet cell adenoma Insulinoma Multiple pancreatic beta-cell adenomas Abnormality of exocrine pancreas physiology Köhler et al. The Human Phenotype Ontology project: linking molecular biology and disease through phenotype data. Nucleic Acids Res. 2014 Jan 1;42(1):D966-74. See Peter Robinson’s keynote on PhenoDay
  26. 26. Mammalian Phenotype Ontology Smith et al. (2005). The Mammalian Phenotype Ontology as a tool for annotating, analyzing and comparing phenotypic information. Genome Biol, 6(1). doi:10.1186/gb-2004-6-1-r7 Used to annotate and query: • Genotypes • Alleles • Genes In mice abnormal pancreatic beta cell mass abnormal pancreatic beta cell morphology abnormal pancreatic islet morphology abnormal endocrine pancreas morphology abnormal pancreatic beta cell differentiation abnormal pancreatic alpha cell morphology abnormal pancreatic alpha cell differentiation abnormal pancreatic alpha cell number See Cynthia Smith’s talk on PhenoDay
  27. 27. Phenotype representation requires more than “phenotype ontologies” glucose metabolism (GO:0006006 ) Gene/protein function data glucose (CHEBI:172 34) Metabolomics, toxico- genomics data Disease & phenotype data type II diabetes mellitus (DOID:9352) pyruvate (CHEBI:153 61) Disease Gene Ontology Chemical pancreatic beta cell (CL:0000169 ) Transcript- omics data Cell Expression and phenotype data Pancreas (UBERON:00 01264) Anatomy
  28. 28. The Biological Spatial Ontology  Evolutionary changes in spatial arrangement  Different standards in different communities =>The Biological Spatial Ontology Gross anatomical directions
  29. 29. The Biological Spatial Ontology Non-perpendicular anatomical axes Cellular anatomical directions Dahdul et al. Nose to tail, roots to shoots: spatial descriptors for phenotypic diversity in the Biological Spatial Ontology. In press, JBMS
  30. 30. Spatial ontology content anterior-posterioraxis anatomicalaxis is_a anteriorside starts_axis posteriorside finishes_axis anterior_to posterior_to opposite_to is_a anatomicalside is_a anteriormargin overlaps anatomicalmargin is_a anatomicalregion is_a anteriorregion overlaps is_a anteriorsurface surface_of anatomicalsurface is_a anatomicalentity passes_through immaterialanatomicalentity is_a anatomicalgradientanatomicalplane sagittalplane is_a midsagittalplane is_a dorsal-ventralaxis approximately_ perpendicular_to is_a anterior-posteriorgradient has_axis is_a orthogonal_to left-rightaxis is_a is_a is_ais_a anatomicalstructure is_a materialanatomicalentity is_ais_a is_a anatomicalboundary is_ais_a anatomicalline apical-basalaxis relativetosubstrate is_a is_a apical-basalaxis relativetodirectionofgrowth is_a
  31. 31. Putting it all together
  32. 32. monarchinitiative.org
  33. 33. Uberpheno – building a cross- species semantic framework Köhler et al. (2014) Construction and accessibility of a cross-species phenotype ontology along with gene annotations for biomedical research F1000Research 2014, 2:30
  34. 34. Uberpheno construction
  35. 35. Uberpheno construction
  36. 36. Uberpheno construction
  37. 37. Uberpheno construction
  38. 38. Facial features are so specific as to enable image based diagnostics iphone App => Uses HPO for annotations
  39. 39. What genotype-phenotype data do we have? GWAS + ClinVar + OMIM Human genes have poor phenotype coverage What else can we leverage?
  40. 40. Human genes have poor phenotype coverage What else can we leverage? …animal data Orthology via PANTHER v9 What genotype-phenotype data do we have?
  41. 41. Combined, human and model phenotypes can be linked to >75% human genes. Orthology via PANTHER v9 What genotype-phenotype data do we have?
  42. 42. Monarch phenotype data Also in the system: Rat; IMPC; GO annotations; Coriell cell lines; OMIA; MPD; Yeast; CTD; GWAS; Panther, Homologene orthologs; BioGrid interactions; Drugbank; AutDB; Allen Brain …157 sources to date Coming soon: Animal QTLs for pig, cattle, chicken, sheep, trout, dog, horse Species Data source Genes Genotypes Variants Phenotype annotations Diseases mouse MGI 13,433 59,087 34,895 271,621 fish ZFIN 7,612 25,588 17,244 81,406 fly Flybase 27,951 91,096 108,348 267,900 worm Wormbase 23,379 15,796 10,944 543,874 human HPOA 112,602 7,401 human OMIM 2,970 4,437 3,651 human ClinVar 3,215 100,523 445,241 4,056 human KEGG 2,509 3,927 1,159 human ORPHANET 3,113 5,690 3,064 human CTD 7,414 23,320 4,912
  43. 43. r Long hallux Midface retrusion Arthrogryposis multiplex congenita Bowing of the long bones Cleft palate Exaggerated Cupid's bow Protruding ears digit 1 phenotype short snout epiphyseal plate morphology abnormal limb long bone morphology Cleft palate Cleft lip lowered ear position Abnormality of toe abnormal head shape Abnormal joint morphology limb long bone phenotype Cleft palate Abnormality of upper lip prominent ears OWLsim: Phenotype similarity across patients or ….any organism https://code.google.com/p/owltools/wiki/OwlSim
  44. 44. https://www.sanger.ac.uk/resources/databases/exomiser/query/exomiser2
  45. 45. Undiagnosed patient 2731 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 -/-
  46. 46. What if there aren’t any similar diseases or other organisms? YARS MARS IARSIL41L AARSIARS2 Abnormal stereopsis Choreoathetosis Microcephaly Akinesia Visual impairment Myoclonus Microcephaly Myoclonus abnormal visual perception Involuntary movements Microcephaly musculoskeletal movement phenotype Patient phenotypes Combined Oxidative Phosphorylation Deficiency 14 FARS2 WARS2 ? AIMP1 UDP_1166 ➔ Exomiser can utilize phenotypic similarity via the interactome
  47. 47. Forward Genomics http://bejerano.stanford.edu/phenotree/public/html/ Hiller et al. 2012 Cell Reports
  48. 48. Connecting baleen and palates
  49. 49. Conclusions  Uberon integrates anatomy across human, model, and non-model organisms  Anatomy and phenotypes can be represented using modular ontologies  We can use the data annotated to these diverse ontologies to support rare and undiagnosed disease diagnosis and explain morphological evolution  Use of semantic similarity algorithms enables candidate prioritization, model identification, and mechanism exploration  Baleen evolution CAN aid disease diagnostics
  50. 50. Acknowledgments NIH-UDP William Bone Murat Sincan Amanda Links Neal Boerkoel Cyndi Tifft Bill Gahl OHSU Nicole Vasilesky Shahim Essaid Matt Brush Bryan Laraway Phenoscape Jim Balhoff Paula Mabee Hilmar Lapp David Blackburn Alex Dececchi Wasila Dahdul Lawrence Berkeley Nicole Washington Suzanna Lewis Chris Mungall UCSD Amarnath Gupta Jeff Grethe Anita Bandrowski Maryann Martone U of Pitt Chuck Boromeo Jeremy Espino Becky Boes Harry Hochheiser EBI David Osumi-Sutherland U of Lausanne Frederic Bastian Univ of Illinois Robert Druzinsky Sanger Anika Oehlrich Jules Jacobson Damian Smedley JAX Cynthia Smith Charité Sebastian Kohler Sandra Doelken Sebastian Bauer Peter Robinson Toronto Marta Girdea Sergiu Dumitriu Orion Buske Heather Trang Mike Brudno iPlant Ramona Walls Funding: NIH Office of Director: 1R24OD011883 NIH-UDP: HHSN268201300036C NSF DBI-0641025, DBI-1062404,

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