Phenoscape Grant Renewal Workshop/Notes

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Phenoscape II: Tuesday, April 28, 1:00-5:30

Participating: Phenoscape: Paula Mabee, Todd Vision, Monte Westerfield, Hilmar Lapp, Wasila Dahdul, Jim Balhoff, Cartik Kothari, Peter Midford, John Lundberg; Suzanna Lewis, Judy Blake, Peter Vize, Anne Maglia

  • Will be extending the taxonomic scope to extant and extinct vertebrates
    • Create an annotation database spanning the taxonomic scope and their anatomy ontologies
    • Three multi-species anatomy ontologies are being developed: teleosts, amphibians, mammalian anatomy
    • Tree mapping: show when an evolutionary phenotype first appeared
  • EQ support in all involved model organism databases
    • Structure of MP is not consistent with anatomy, or with PATO
    • Mapping from MP to EQ syntax is being worked on (George Gkoutos)
      • How is this supported in MGI?
        • Could spit back EQ, but could not allow users to search
    • MGI isn't in a position to use EQ internally, but for example Phenoscape II could provide an EQ-view on mouse phenotypes, using the decomposition of MP into anatomy (or entity) and quality term cross-product
    • Full EQ annotation for OMIM is being planned but not yet funded
    • MGI, Xenbase, and ZFIN all have links from their phenotype data to OMIM
  • Phenoscape II: Development of anatomy - new queries supported; would generate testable hypotheses; how exactly do those queries rely on developmental data?
    • Different approaches between MGI and ZFIN:
      • MGI uses complete anatomy at different developmental stages
      • ZFIN uses one anatomy ontology and adds start and end dates to indicate the developmental period during which it appears (adult structures don't have an end date)
      • Xenbase uses the ZFIN approach
    • Candidate genes for evolutionary change could be derived from anatomy-annotated gene expression studies during development; Where do mouse and Xenopus share gene sets in early development?
      • genes responsible for or associated with morphological changes during individual development could be candidates for evolutionary change
      • evolutionary phenotype changes could be used to query morphological changes during development
    • Can we enable queries to generate hypotheses based on ontogeny reflecting evolutionary history?
    • Powerful tool in interpreting microarray data downstream from node; know candidate genes without mutants using this approach
    • See phenotypic differences between 2 taxa – where do you see similar changes?
    • Cell types and associate with time and space – can reason from, neural crest, etc.
      • Evolutionary developmental data could come from medaka, stickleback
  • Sequence of steps:
    1. Ontology building
      • Adult phenotype annotations for mutants in Xenbase
      • Presently only 3 species for amphibians: Xenopus, Dermophis, Salamandria (integration beginning in July; phenotypes/mutants, adulta; L. Zimmerman (GB))
      • Development decoupling from anatomy ontology in mouse (as per above)
        • Requirements:
          • QC required – 1 person to find orphans and generate reports (80% complete); make decisions
          • 1st: alignment of MP and mouse anatomy, then QC of MP-EQ; use Mouse anatomy to initalize Paul’s ontology
          • 2nd: Mouse staging-> ZFIN + Xenbase style
          • Phenoscape II: Time required for above (1st and 2nd) is 1 person over 3 years
      • Expanding mammalian anatomy to include extinct species
          • Judy mentioned Fiona McCarthy (chick ontology? Judy will ask)
      • Anatomy for amniotes (the clade including mouse and dinosaurs), including extinct taxa (such as dinosaurs)
        • Scope of this could be overwhelming
        • Should be strongly driven (or staged) according to the character matrices to be annotated
        • Chicken anatomy could provide a starting point?
        • There is work on bird anatomy that uses a latin naming scheme
        • Work on any smaller-scope anatomy (or multi-species anatomy) ontology will contribute terms that apply more broadly
        • There may not be very many neomorphs between birds and mammals, though there are a few areas such as the digits in birds where the exact homology relationships aren't as clearly agreed upon.
        • set up ontology and extend to fossils that Paul knows best;
        • also need taxonomy onotlogy (from suprageneric filemaker database?)
    2. Mammalian phenotype decomposition
      • Need support for QC'ing the results of automated decomposition
      • Alignment of MP with mouse anatomy
    3. Annotation
      • Which published character matrices are there for dinosaurs?
  • Ontology mapping and alignment
    • Need to align teleost and amphibian anatomy to mouse.
    • Mouse and chicken need to be mapped to amniote anatomy. Mouse is a better start because there are genetic data.
  • Paul Sereno gave short presentation on reconciling character-derived trees and character definition and use between different matrices and trees that share taxa
    • TaxonSearch
    • Formalizing and generating grammar of character coding and character state definition
      • Phenoscape II grant activity could be to produce EQ primer
    • presented summaries of annotations, by region, by authors, by structure, by quality
    • Paul’s question: Why are 2 trees different? A: Particular characters and types of coding; If you are trying to develop a consensus tree – can see how authors’ differ
    • Analyzing character usage (shared, not shared, rejected) between trees that share taxa
    • Conflicting phylogenies for the same set of taxa often turn out to be based on character codings that are not consistent or not compatible
    • need to not only curate legacy data but be proactive in terms of syntax etc. of future data; use cases looking forward; morphology in crisis, wallowing in a sea of data
  • Re: direct submission --Monte: ZFIN has 6,000 users, but 4-5 labs do direct submission of a lot of data; he suggested Phenex modified as a web tool to put in data; also ontology modification/use of Mesquite

  • Miscellaneous discussion following above (Tuesday pm)
  • Open to communities
    • Phenoscape has public data, but can upload private data and use visualization tool
    • working environment enabling exploration of data for analysis
    • would allow people temporarily to overlay on whole data store
  • NCBI blast similarity – phenoblast
    • Will need term tracker
    • Monte: Issue of best practice for global size/shape
    • Todd: (here is forest of EQs that match)
      • can move up and down ontology
      • shape and syntax; best practice
  • Discussion of images (linked to AO, PATO) – definitional, put in ontology; browsing, finding right AO term
    • could call for images in particular sets of species
  • Are ontologies useful for phylogenetics? ATOL data and relationships are a challenge (Paul)
    • Can a matrix be reconstructed and can data be related in an effective way?
    • Do ontologies serve this community well?
    • Limiting from community?
    • Explore whether useful for phylogenetics?
    • Capability of characters for phylogenetic studies?
  • Viability of PhenoscapeII depends on morphologists using it!
    • vast phylogenetic branches – does character annotation at gross level conceal or reveal phylogenetic information?
    • Can we retrieve the characters that are discordant?
  • What question motivates character matrix?

Developmental time & misc discussion

  • Development of mouse and Xenopus:
    • Notochord in adult example
  • Phenoscape II: create developmental time ontology for vertebrates.
  • Compare heterochronies:
    • relative ordering of entities and associated gene expression
    • Anne’s example of heterochronic frogs…
    • Notochord-hedgehog at particular times & wnts
  • For a given evolutionary change, what are genes expressed in a time at a place?
    • pick ~ 12 terms and make table and map for multiples species
  • Phenoscape and vertebrate development ontology (?)
    • would facilitate finding genes responsible
    • without start and stop times, would have develops_from only
    • enables placement of a phenotypic information into a developmental framework; develops_from
    • what are the sets of characters that evolve at derived condition; see how phenotypic characters cluster at particular branch points; even do math, counting nodes; can do stats at branch points.
    • creating diff definitions of homology; try to experimentally differentiate species
  • Evolutionary time: use cases; compare sister groups
    • Rates
    • Dating clades – minimum age
  • Database discussion – Todd/Jim
  • OBD – Suzi – Need to work on ability to pull things back on basis of similarity; on basis of phenotype – what else is there that affects a bone?
  • Suzi & co. would adopt single searches by gene or body parts
    • Cartik: Support units and measures
    • Jim: User see OBD structure – enter a term and visualize EQ annotations in relation to it;
    • See Ensemble – Phenoscape Mammals; Phenoscape Amphibs; Phenoscape Fishes – Allow user to move between taxonomic stashes without mapping
    • Sparkle: Chris: issue generic queries – return data in generic format
    • Suzi: Allow people to add term if they are making query and not finding anything
      • could repurpose protein tree/ GO
      • relative ordering of entities and associated gene expression

Wednesday morning, April 29, 2009

  • Expanding taxonomic coverage to Vertebrata
    • Phenoscape has about 15,000 species of teleosts untouched (half that number is sampled in a typical study) and approx 200 matrices to target
    • Amphibanat estimates 3,000 amphib species and approx 36 matrices
    • Plan to maintain skeletal focus for anatomy development
  • How best to keep nomenclature history?
    • Nomenclatural history of terms in ontologies
    • mechanism to keep track of in OBO-edit? No
    • keep track of this information on the database side
    • Current exchange format standards don't support this really beyond obsoletion
    • ZFIN tracks within the database the complete nomenclatural history of gene names; (ZFIN records the reason, comments etc…in database comments)
    • RDBOM tracks literature and author attribution for anatomy terms but not yet nomenclatural history
      • Amphibanat handles comments with fields:
        • Is_defined_by:
        • Is_discussed_by:
        • Literature citations are an ontology linked to other concepts
  • Character quality profiles for data matrices
    • Addresses the question of "Where in the skeleton are the changes occurring that drive the phylogeny"
    • Distribution of characters across the skeletal anatomy, at different levels of the hierarchy
    • Distribution of missing data across the anatomy, at different hierarchy levels
    • How many taxa have how much missing data, distributed on which anatomical parts
  • DRIVING QUESTIONS:
    • What parts are of phenotype are variable a) in particular taxonomic groups; b) in particular author’s studies?
      • Where are the gaps in character variation? In taxon sampling?
      • Why are there gaps in phenotype variation? Missing data, fossils
      • What is not changing – not in matrix –
      • Because extinct not in fossil record (no a??)
      • Or constrained (just no variation)
      • To get at redundancy, have to factor in taxonomic sampling and character sampling.
    • Q: Who much is good data? How much is redundant?
      • What is redundancy? Identical EQs? Action: curate to fine grain in order to match; develop tool to be able to see other EQ annotations
    • Q: How does the order of development correspond to the order to evolution?
  • Use case: Character redundancy
    • Deriving a character profile across the anatomy could help visualize the redundancy between annotations
  • Use case: Mapping the evolutionary characters that lead (and distinguish) to a model organism. Subsequently, see whether these evolutionary changes and the order in which they appear to the ontogeny of the organism.
    • Will need to deal with character gaps and with character redundancy for this.

Specific goals:

  1. Expand taxonomic coverage of Phenoscape to Vertebrata
    • Mouse is done but needs to be rearranged (MP decomposition)
    • Amniotes need to be done from the ground up


Wednesday afternoon

  • Problem of lossy transformation of legacy character data
    • EQ annotation is often at a lesser granularity (or level of detail) than the original free text description
    • This isn't due to any technological obstacles but rather due to the limited resources available for annotation.
    • Annotation effort is best focused to a granularity level where it suffices to solve a use-case of interest.
    • Annotating at very granular levels is entirely possible but can take a lot of time because many of the ontology terms needed are likely not to be present yet in the ontology.
    • How does this impact phylogeny and data matrix reconciliation, or phylogenetic reconstruction on the basis of the EQ annotations?
  • Use-case for development
    • Heterochrony would be interesting if one can pull it out of the database
    • Ordering of developmental landmarks uses develops_from; Developmental ordering relationships currently used are confined to develops_from and transforms-into.
      • This is missing yet for mouse.
      • Wouldn't really allow inferring heterochrony.
      • Would allow though to place and compare the placement of phenotypes into a developmental chain of transformations.
    • Use case to compare sequence of ossification in ontogeny of an individual vs. among species variation in degree of ossification of a structure; idea is to visualize where these structures are on the developmental sequence of a MOD
    • Homology and develops_from:
    • Juvenile wing primordiium homologous to adult limb?
    • John: should add the phrase to any homology statement: “two things are homologous as _______”
  • Evolutionary time:
    • TimeTree www.timetree.com; pairwise comparisons to get ages
    • Questions that can be asked regarding geologic time:
      • How far back in time do you need to go to find a particular change in phenotype?
      • Does this type of character change occur during a particular time period?
        • Requires trees
  • Informatics: what do you want to see?
    • Cartik: measurements displayed in web interface (it’s supported in Phenex and OBD currently)
    • Jim: user upload; group annotations and click through neigborhoods…see Hilmar notes
  • Tree visualization
    • Nodes don’t have ancestral state reconstruction, they are the union of phenotypes in the database; displays all the phenotypes that are recorded in a clade, not mapping of characters.
    • PhyloWidget developed in 2007 summer of code
      • Annotate parts of the tree with images, phenotypes, etc.. to a tree topology
    • Character optimization for Phenoscape II
      • Optimizing EQs involves deciding which EQ is alternative to another
      • Todd: Easier for user to download data and create matrix on their own
  • Phenex stuff:
    • Add skeletal parts in association with museum voucher for paleo data; for extant dry skeletal vs. cl/st. Could help discern WHY, e.g., cartilage is not variable in data matrix.
  • Demonstration of Phenoscape KB
    • Some of the features we are developing (the 3 principle queries) would be very useful to MOD users
  • Informatics goals for Phenoscape 2:
    • Supporting units for measurements
    • Allowing others to compare their phenotype data to the knowledge base
    • Generic ontological queries, such as a SPARQL endpoint
    • Private data overlay
    • Linked Data and semweb integration
    • Tree visualization
    • Triple store technology evaluation
    • Species ID
    • Phylogenetically informative distance metric based on EQ assertions
    • NLP-based text processing, Mass curation

Idea bin

  1. Intermine connection (multiple model organisms, AJAX-based widget for displaying protein family tree)
  2. Some phenotypes imply developmental abnormalities, differences, or variation.
    • For example, a "poorly ossified cranium" in an adult amphibian implies that the developmental process was delayed or did not complete.
  3. How does logical inference of homology propagate over develops-from relationships.
    • E.g., if A and B are asserted homologous, and C develops from A and D develops from B, are then C and D inferred as homologous, and are C and B inferred as homologous.