Donna Maglott, PH.D.

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PRO and Medical Genetics resources at NCBI

• Donna Maglott, PH.D.

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Opportunities

• The medical genetics group is a relatively recent
  addition to the suite of resources at NCBI, and
  manages the NIH Genetic Testing Registry (GTR),
  ClinVar, and MedGen.  These databases share the
  need to standardize representation of genes,
  proteins, small molecules, variation, conditions,
  and phenotypes, not only with respect to explicit
  terms, but also the relationships among those
  terms. This presentation will focus on
  opportunities for utilization of PRO in the
  NCBIs Medical Genetics group.

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Case studies

• Medical genetics ClinVar, Gene, GTR, MedGen

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A quick tour
From the home page
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Using the resource sections
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Try all sections
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Try all sections
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major domains of information
Concept NCBI database/Resource Used in
Diseases and their defining features MedGen (Diseases, Findings) ClinVar, dbVar, Gene, GTR, PheGenI, dbGaP
Drugs MedGen (Pharmacologic Substance) ClinVar, GTR
Genes and gene products Gene, Nucleotide, Protein, HomoloGene, RefSeq ClinVar, dbSNP, dbVar, GTR
Biological processes, cellular components, molecular functions --- Gene
Interactions and pathways Biosystems, Gene Biosystems, Gene
Variation ClinVar, dbSNP, dbVar ClinVar, dbSNP, dbVar
Records connected by reciprocal, generic links
via database identifiers
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Some Talking points

• Except for RefSeq, curation minimal
• RefSeq-based with pointers to UniProtKB
• Use ontologies to acquire and represent standard
  terms
• Point to ontologies, but not used to support
  node-based query interfaces
• Capturing primary data that can be used to drive
  development of ontologies
• Some user communities think in terms of
  nucleotide only
• Data being submitted with uncertain significance
• Look for opportunities for adding value to NCBIs
  databases and tools

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Gene and data standards

• Name of the gene (nomenclature committees)
• Names of protein products
• Primary product (Swiss-Prot)
• Isoforms (RefSeq)
• Names of associated conditions (multiple)
• Descriptions of pathways (submitters)
• Biological processes, cellular components and
  molecular functions (GO)
• HIV interactions (NIAID)
• http//www.ncbi.nlm.nih.gov/gene?termhiv1interact
  ionsProperties
• http//www.ncbi.nlm.nih.gov/projects/RefSeq/HIVInt
  eractions/

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Human mismatch repair
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Restrict to those reported to be disease-causing
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www.ncbi.nlm.nih.gov/gene/4292
Summary Bibliography Interactions Pathways Gene
Ontology General protein information Reference
sequences Locus-specific databases
Phrase found in
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Titles of pathways Descriptions of interactions
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(No Transcript)
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Genelt-gtProtein
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HomoloGene
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Diseases and phenotypes

• MedGen UMLS, HPO, OMIM, ORDO, GTR

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Why MedGen?

• A stable node of identifiers within NCBI for
  disease names, their clinical features, and
  pharmacological substances
• Built on the foundation of a subset of UMLS, with
  supplements from HPO, OMIM (between UMLS
  releases), and submissions to GTR and ClinVar
• Primarily automated, but some overview by M.D.s
  and genetic counselors on staff, and feedback
  from the community

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Terms from UMLS/OMIM/GTR/ClinVAr
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HierarchieS curated by GTR staff
Guided by OMIMs clinical series and user feedback
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Hierarchies computed from nodes in UMLS
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Hierarchy from DNA Repair Deficiency Disorders
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Using HPO for Clinical features

• Partial display
• Organized by top nodes of the ontology
• Each specific term supports a link to disorders
  manifesting that feature

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Clinvar reported variation-phenotype relationship
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Clinvar reported variation-phenotype relationship

• Submitter archive (not curated)
• Variant
• Disease and/or phenotypes
• Interpretation
• Confidence

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Subset of a detailed record

• Gene name and symbol
• Sequence ontology for molecular and functional
  consequences
• Diseases
• Identifiers and links
• Observed phenotypes (as distinct from those
  reported to be characteristic of the diagnostic
  term)
• Protein change from the variant

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Data sources and growth
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Submissions from UniProt
Summarize submissions by genes, diseases, and
phenotypes
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Current status clinGen-related

• Diseases
• Genes
• Variants
• Predictions
• Conserved sequence
• Conserved domains
• Pathways

http//www.clinicalgenome.org/
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Phenotype anD clingen/ClinVAr

• Working group on phenotype
• Make distinctions among
• Disease category (body system, metabolic
  perturbation, cancer)
• Diagnosis
• Characteristic features
• General or gene-specific
• Diseases targeted by drugs for which the response
  is genetically determined
• Observed phenotypes
• HPO
• PhenoDB
• Indications for testing
• Standardization
• One ontology or many?
• Relationship to OMIM

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Variation and CliNGEN/ClinVar

• Sequence Ontology for variant location and effect
• Coordinate with PharmGKB for pharmacogenomics
• Description of haplotypes
• No discussion yet about authorities for pathways,
  conserved domains, post-translational
  modifications

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Current Status NCBI

• Working with UMLS to improve representation of
  terms and relationships
• Mapping concepts
• Reporting relationships
• Supplement current UMLS with HPO, Orphanet (ORDO,
  in progress), and recent data from OMIM
• Working with Clinical Pharmacogenetics
  Implementation Consortium (CPIC) and PharmGKB
• Representation of haplotypes/star alleles
• Drug responses/Disease target
• Consumer of ontologies to standardize
  terminology, with definitions
• Link to resource site
• Provide attribution
• Support term-specific queries

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Current Status NCBI

• Queries currently term by term, not by node
• Some relationships based on links in Entrez
• Gene lt-gtdisease
• Disease lt-gtclinical feature
• Variation lt-gt gene
• Some relationships explicit
• Genome-gttranscript-gtprotein
• Nucleotide change-gtprotein change
• Some relationships reported as hierarchies
• GTR
• MedGen (MeSH)
• ORDO (in progress)

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Current Status NCBI

• Maintenance
• primarily automatic
• Some curatorial review by staff of ClinVar and
  NIH Genetic Testing Registry (GTR)
• Expect expanded review from the ClinGen group
• Data freely available by ftp or E-utilities
• ftp//ftp.ncbi.nih.gov/pub/clinvar/
• ftp//ftp.ncbi.nih.gov/gene/
• ftp//ftp.ncbi.nih.gov/pub/GTR/
• ftp//ftp.ncbi.nih.gov/pub/medgen/

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Acknowledgements
Slava Gorelenkov MedGen
Melissa Landrum ClinVar
Jennifer Lee GTR, ClinVar
Terence Murphy Gene
Lon Phan dbSNP/dbVar
Kim Pruitt RefSeq
Wendy Rubinstein GTR, MedGen
Ming Ward dbSNP
and all their staff and all their staff