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The C onsensus C o D ing S equence (CCDS) Database

The C onsensus C o D ing S equence (CCDS) Database. Kim D. Pruitt Mouse Genome Annotation Summit Meeting March 12-13, 2008. Why is the CCDS project needed? . The Problem : Annotation of the genome sequence is essential – but beware of different interpretations!.

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The C onsensus C o D ing S equence (CCDS) Database

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  1. The Consensus CoDing Sequence (CCDS) Database Kim D. Pruitt Mouse Genome Annotation Summit Meeting March 12-13, 2008

  2. Why is the CCDS project needed? The Problem: Annotation of the genome sequence is essential – but beware of different interpretations! • The availability of the human and mouse genome sequence has had a significant impact on disease and health research. • Most scientists rely on annotation information when designing, interpreting, and evaluating research results. • Inconsistencies in annotation results among the main public resources hampers use of this important data. • Researchers may not realize that a different annotation result is available elsewhere – possibly leading to erroneous or incomplete interpretations.

  3. Initiated by the main public annotation/browser groups to address concerns by the scientific community about inconsistencies in the human and mouse genome annotation. Built by consensus among the collaborating members, which include: European Bioinformatics Institute (EBI) National Center for Biotechnology Information (NCBI) University of California, Santa Cruz (UCSC) Sanger Institute (WTSI) CCDS - A collaborative project

  4. Project Goals identify a core set of protein-coding genes that are consistently annotated and of high quality support convergence toward a standard set of gene annotations Scope: Human and mouse protein coding regions Update frequency Variable Depends on frequency of genome annotation updates What is the CCDSproject?

  5. Processflow – calculating updates NCBI (computational) Havana (manual) Ensembl (computational) RefSeq (manual) Compare CDS (Annotation + Sequence) Ensembl merged annotation QA

  6. Quality assessment tests include: Consensus splice sites ("GY..AG" or "AT..AC") Valid start and stop codons with no internal stops NMD Low complexity Repeat-containing Insufficient protein homology Genome conservation Putative pseudogene Assessing Quality • CCDS status is conservatively applied: • Annotated CDS coordinates are identical • Annotation is of high quality and passes QA tests, or curator review • Existing CCDS proteins can be flagged for review by the collaborating members • Updates and removals are by consensus agreement. • QA test results are reviewed by curators • Over-rides are set to retain supported CDSs

  7. CCDS Counts Step Source Genes Proteins Annotation NCBI 24765 26851 Annotation Ensembl 27209 39941 Matching CDS 18185 19048 QA & curation rejections 1331 1350 Accepted rejections 1292 1341 Final CCDS ID 16893 17707

  8. Any member of the collaboration can flag a CCDS for review Update the CDS definition (alter N-terminus extent internal splice site) Withdraw the CCDS ID (insufficiently supported, or non-protein coding) NCBI provides a collaboration web site to coordinate this review All collaborators must agree with a change to finalize a decision Withdrawal of a CCDS may happen between genome annotation updates An update to a CCDS is indicated by: Status change: a status of ‘pending update’ is reported when there is collaborative agreement that a change is needed Version change: The CCDS version number is incremented once the change is reflected in public annotation. This only occurs after a genome annotation update and CCDS analysis has taken place. CCDS curation is fully integrated with RefSeq curation Curation – how are updates curated and coordinated?

  9. name action status count human update pending 366 human update agreed 557 human withdraw pending 189 human withdraw agreed 519 mouse update pending 185 mouse update agreed 57 mouse withdraw pending 16 mouse withdraw agreed 8 name build status count human 35.1 Withdrawn, inconsistent annotation 133 human 36.2 Withdrawn, inconsistent annotation 29 mouse 36.1 Withdrawn, inconsistent annotation 29 mouse 37.1 Withdrawn, inconsistent annotation 4 CCDS update & curation stats Curation-based changes: Mouse: ~5200 curated CCDS genes 923 709 242 24 Annotation pipeline-based changes:

  10. Alignments Track low quality sequences (‘kill list’) Protein conservation Publications Personal communications QA measures Curation considerations

  11. Genome browser displays NCBI UCSC Gene reports Ensembl NCBI UCSC Vega Other: RefSeq annotation (NCBI) CCDS web site FTP http://www.ncbi.nlm.nih.gov/CCDS/ Access – How do I know if an annotation has a CCDS ID?

  12. NCBI Map Viewer (chr.5) Link to CCDS Browser

  13. UCSC Browser chr5:30270000-30650000

  14. UCSC Browser – Tyms gene CCDS Browser

  15. Access of CCDS data at NCBI • CCDS Database & Browser interface • Project Description • Query support • Reports attributes of the CCDS • Location data • Sequence members • Status • FTP reports

  16. CCDS Browser History Find all CCDSs for the Gene Entrez Gene View CCDS Details

  17. Mouse-over highlights codon • Click to highlight codon and corresponding amino acid CCDS Browser

  18. 1 vs 2 vs ‘n’ genes translation start site Biology is complex – some CCDS curation examples

  19. Curation Considerations: Nomenclature History (scientific use, publications, etc.) Different (but similar) products vs. distinct products Shared promoters 1 vs. 2 vs. ‘n’ genes

  20. carnitine palmitoyltransferase 1b, choline kinase beta

  21. Current RefSeq representation of the region - two protein coding loci - one non-coding loci for the non-coding transcript product (a read-through transcript) 1 vs. 2 vs. ‘n’ genes Chkb (CCDS27750.1) Cpt1b (CCDS27749.1 ) Chkb-cpt1b (PMID:12761301 )

  22. Curation Considerations Publication reports (CDS begins at ‘n’) Other cDNA sequencing reveals the ORF can be extended further upstream Evaluate: Genome conservation Literature reports for the protein Putative Kozak signals Presence of in-frame upstream stop codon INSDC submissions from an experimental lab source that do have the longer ORF extent annotated. Consult with an expert Translation start site

  23. Internal CCDS browser (restricted access) Jmjd2d jumonji domain containing 2D (chr 19)

  24. Update is agreed on by all parties Resulting in a 258 aa N-terminal extension

  25. Examples – no CCDS ID EBI+WTSI and NCBI transcript annotation may differ even though the gene includes annotations with CCDS IDs

  26. Examples –no CCDS ID • Reasons: • not found by one group • different CDS length • different splice sites • different internal exon • Curation removal EBI/WTSI NCBI EBI/WTSI NCBI EBI/WTSI NCBI EBI/WTSI NCBI

  27. Acknowledgements • Collaborators at Ensembl, UCSC, Vega • Jen Ashurst & Vega curator group • Rachel Harte • Mark Diekhans • Steve Searle Donna Maglott Josh Cherry Keith Oxenride Craig Wallin Andrei Shkeda RefSeq Curators NCBI Genome Annotation Group NCBI Map Viewer Group

  28. Ensembl – Tyms gene

  29. Vega browser Tyms gene (chromosome 5 30388989-30404404)

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