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Lrg and mane 16 oct 2018

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Lrg and mane 16 oct 2018

  1. 1. How does it relate to MANE and GRC? The Locus Reference Genomic (LRG) project Joannella Morales, PhD Project Manager EMBL-EBI jmorales@ebi.ac.uk
  2. 2. • Joint effort between the NCBI and EMBL-EBI since 2008 • Recurrent requests from clinical community for tools to ensure efficient and consistent variant reporting • Challenges: • Keeping track of clinically-relevant variants over time • Changes to genome assembly • Changes to genes and transcripts • Inconsistent reporting of variants due to lack of approved/standardized sequences • Multiple genomic haplotypes • Multiple transcript sets • Multiple versioned sequences The LRG Project For example, PAX6 (eye) 11 NMs 81 ENSTs Which sequence to use??
  3. 3. LRG records • Manually curated • Contain stable reference sequences (do not version) • Sequences selected by curators in collaboration with locus-specific experts • Used for reporting of clinically-relevant variants – HGVS compatible • Genomic - LRG_1:g.15178G>A • Transcript - LRG_1t1:c.2156G>A • Protein - LRG_1p1:p.Gly719Asp
  4. 4. LRG Records
  5. 5. LRG and MANE convergence • LRG Project not scalable since it is 100% manual and there are thousands of clinical genes • Automation useful, but manual oversight required to ensure meaningful in the clinical context • Evolution of LRG -> MANE Plus? • Same methodology as MANE project • Extended to cover transcripts that are well-supported, tissue-specific or relevant to specific user groups; a cut of the highest value representing most exons with well-expressed splice forms • LRG Team • Manual effort to review transcripts for MANE Plus? set • Engage with locus-specific experts • Continue to support existing LRG records
  6. 6. LRG and GRC • LRGs are independent of GRCh38 • Many LRG users require or prefer alternate sequences • Issues in GRCh38 (e.g. ABO) • GRCh38 represents a minor allele (e.g. HTT, EIF2AK3) • Vast majority of LRGs match GRCh38, but several LRGs contain non-GRCh38 sequences
  7. 7. Annotation about mismatches When the GRCh38 allele is not the preferred allele
  8. 8. LRG and GRC • This user group cannot be served by MANE project (due to GRCh38 dependency) • LRG project will continue to create records for genes where an alternate genomic sequence is required • LRG project will continue to work with GRC to create Novel patches, when possible
  9. 9. Questions?

Editor's Notes

  • Describe rationale for LRG project, why it started
  • Show LRG records
  • Discuss how LRG relates to MANE

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