1. Managing Big Scientific Data Capturing, Integrating and Presenting Mouse Data at MGI Cynthia Smith Canberra April 2010 www.informatics.jax.org Mouse Genome Informatics

2. short domed skull short-limbed dwarfism malocclusion bulging abdomen as adults respiratory problems shorted lifespan Achondroplasia Homozygous achondroplasia mouse mutant and control Mouse Genome Informatics (MGI) program goal …to facilitate the use of the mouse as a model for heritable human diseases and normal human biology.

3. …to accomplish MGI’s mission, we provide integrated access to the genetics, genomics, and biology of the laboratory mouse. Hermansky-Pudlak syndrome Information content spans from sequence to phenotype/disease sequence natural variation gene function genome location orthologies strain geneaology expression tumors

4. MGI Data Content, a few numbers April, 2010 Genes (including uncloned mutants)36,691 Genes w/ nucleotide sequence29,108 Genes annotated to GO Total mouse GO annotations 25,620 223,558 Mouse/human orthologs17,846 Mouse/rat orthologs16,776 Phenotypic alleles in mice genes with mutant alleles in mice mutant alleles in cell lines only total phenotype annotations (Mamamlian Phenotype-MP) 24,007 12,427 541,172 182,139 QTL4,436 Human diseases w/ one or more mouse model1005 Gene Expression Assays37,584 Integrated mouse nucleotide sequences+ESTs refSNPs >9,994,000 >10,089,000 References153,161 …plus strains, expression and phenotype images, tumor records, etc.

5. Integration in MGI Identify objects. Resolve discrepancies. Integration is key to knowledge discovery

6. Integration is hard…not just a matter of combining data sources… Data from multiple sources can be of differing quality The same data can enter the system via various paths Naming conventions may or may not be to standards Some data sources don’t maintain unique accession numbers (or allow them to change) Periodic updates from data sources can cause problems if objects have disappeared… (or reappear) If objects have split in two

7. Data Acquisition Object Identity Standardizations Data Associations Integration with other bioinformatics resources Literature & Loads New Gene, Strain or Sequence? Controlled Vocabularies Evidence & Citation Co-curation of shared objects and concepts Annotation Pipeline

8. Data integration is hard “Bucketizing” establishe types of correspondence between objects in the input sets. Allows immediate incorporation of 1:1 corresponding data. Sorts conflicting data into bins that allow prioritization for curator resolution.

9. VEGA annotated three distinct genes instead of multiple transcripts for a single gene (Mvk) chr5:114705285-114721583

10. Why resolve and integrate data? 1. Allows you to find all the data: Example: I want all the sequences from GenBank that are from C57BL/6 There are >100 different versions of this strain name in GenBank files, e.g. B6BL/6C57BL76J57BL/6J Black-6JB6C57Black/6black six …..ETC… Example: You find several papers describing different phenotypes of knockouts of the Fgfr2 gene. The knockout alleles are just called Fgfr2 -/-. Help! There are 14 different targeted alleles of Fgfr2 (knockout/knockin, each has a unique symbol and MGI-ID, different phenotype annotations, and are models of different human diseases). All are associated with their respective references. MGI has curated these data. You can ask these questions!

11. Why resolve and integrate data? 2. Allows you to discriminate ambiguous data Example: I want information for mouse gene Tap Which gene? There are 5 genes published as Tap. Each of these genes has Tap as a synonym. Chr 15 Ly6a, lymphocyte antigen 6 complex, locus ALy6a Chr 19 Nxf1, nuclear RNA export factor 1 homolog (S. cerevisiae)Nxf1 Chr 11 Sec14l2, SEC14-like 2 (S. cerevisiae)Sec14l2 Chr 17 Tap1, transporter 1, ATP-binding cassette, sub-family B (MDR/TAP)Tap1 Chr 5 Uso1, USO1 homolog, vesicle docking protein (yeast)Uso1 P.S. Gene Gnas has 20 synonyms

12. Why resolve and integrate data? 3. In addition to object identification issues, integration allows you ask complex questions that span data sets and data types from different sources: Example: What genes on Chromosome 11 have mutant alleles that display phenotypes of hydrocephaly and hypertension? Example: Provide me with a list of Refseq IDs where the gene corresponding to the sequences show expression in embryos at 13.5-15 days and are involved in the biological process (GO) of apoptosis.

13. Integration requires consistent semantics Controlled vocabularies/nomenclatures Strains Genes Alleles (phenotypic or variant) Classes of genetic markers Types of mutations Types of assays Developmental stages Tissues Clone libraries ES cell lines ….. organized as lists or simple hierarchies

14. Ldb1 (LIM domain binding 1) gene expression in CD-1 mice Assay Type Gene nomenclature Strain Age Results

15. Semantics plus relationship data Ontologies/structured vocabularies Gene Ontology (GO) Molecular function Biological process Cellular component Mouse Anatomy (MA) Embryonic Adult Mammalian Phenotype (MP) Sequence Ontology (SO) ….. organized as directed acyclic graphs (DAGs) DAGs

16. Mammalian Phenotype Ontology Structured as DAG Over 7324 terms covering physiological systems, behavior, development and survival Available in browser and in OBO file formats from MGI ftp and OBO Foundry sites

18. P05147 PMID: 2976880 GO:0047519 IDA P05147GO:0047519 IDA PMID:2976880 GO Term Reference Evidence Annotating Gene Products using GO Gene Product

19. Data sources Primary literature Centers: mutagenesis, gene trap, etc Data Loads: GenBank, SNPs, clone collections, UniProt, RIKEN, IKMC,etc Electronic Submissions (individual labs) Processing, QC, and curation Gather data from multiple sources Factor out common objects Assemble integrated objects

20. Data sourcing for MGI Data from major providers (e.g. Ensembl, UniProt) and from data project Centers (e.g. gene trap, ENU mutagenesis centers) are generally reliably formatted, though data may still have QC issues. Occasional changes in format can be frustrating. Data from individual research labs vary greatly in file formats and adherence to nomenclature & usually are handled on a case-by-case basis. Scientific literature is a reflection of individual labs (largely), & must be treated as using non-standard nomenclatures – but awareness is improving!

21. Data sourcing for MGI (…wishes) more user contributions pre-publication nomenclature assignments data submissions (data can be held private until publication) journal permissions for images - have some in progress (collaborations on raw phenotype data exchange with European and Japanese mouse mutagenesis and knockout groups)

22. Building a mouse phenotyping data resource Large scale ENU mutagenesis programs worldwide - continuing Large scale gene trap programs (International Gene Trap Consortium) www.genetrap.org - gene trap cell lines loaded, with Lexicon www.genetrap.org International Mouse Knockout Consortium KOMP – Knockout Mouse Project (USA) www.knockoutmouse.orgwww.knockoutmouse.org EUCOMM – European Conditional Mouse Mutagenesis www.eucomm.orgwww.eucomm.org NorCOMM – North American Conditional Mouse Mutagenesis http://norcomm.phenogenomics.ca http://norcomm.phenogenomics.ca Texas Institute for Genomic Medicine Knockouts www.tigm.orgwww.tigm.org Collaborative Cross www.complextrait.orgwww.complextrait.org Literature and lab submissions New recombinase (cre, flp, etc) and reporter database is online and data is being populated

23. BREADTH: Large scale screen for potential phenotypic outliers DEPTH: Phenotypic description of mutant genotype(s)

24. SUMMARY Integration in MGI is accomplished through a combination of automatic & semi-automatic loads & QC processing, followed by manual curation. requires applying semantic consistency using standard nomenclatures, ontologies and structured vocabularies. provides users with the ability to find data that would otherwise not be found or ambiguous. allows complex questions spanning different data sets and data areas to be asked.

25. SUMMARY Data Sourcing in MGI includes data from major genome resources and mouse centers, as well as individual lab submissions and curated information from scientific literature. requires QC processing for format consistency; for some (individual) labs case-by-case assistance. for new large-scale phenotyping activities, integrate data with common curation of MP ontology; connect with raw data (international collaboration). continue to work with community and journals to allow easier data access.

26. Bar Harbor, Maine MGI is funded by : NHGRI grants HG000330, HG002273, HG003622 NICHD grant HD033745 NCI grant CA089713 www.informatics.jax.org