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Ashg2015 schneider final
The document discusses the human reference genome assembly GRCh38. It provides information on assembly basics, the assembly model used, updates made in GRCh38 compared to the previous version, and how to access and utilize the sequence and annotation data. Key points include that GRCh38 represents 178 genomic regions with alternative loci sequences, contains over 400kb of novel sequence from targeted updates, and is collaboratively maintained to integrate new data.
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Ashg2015 schneider final
- 1. Getting the Mostfrom the Reference Assembly Valerie Schneider, Ph.D. NCBI 6 October 2015 http://genomereference.org
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- 3. Outline • Assembly basics •The assembly model • GRCh38 & updates • Taking advantage of the data
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- 6. Sims et al.(2014) Nat Rev Genet. 15(2):121-32 30x 1x Reference Assembly Basics Lander and Waterman (1988) Genomics SequencedNot sequenced 1X Coverage 5X Coverage 10X Coverage 37% 63% 0.6% 99.4% 0.005% 99.995%
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- 8. BAC insert BAC vector Shotgunsequence Assemble Foldsequence Gaps deeper sequence coverage rarely resolves all gaps GAPS “finishers” go in to manually fill the gaps, often by PCR Clone based assemblies Reference Assembly Basics Minimal Tiling Path
- 9. Human assemblies availablein the NCBI assembly database http://www.ncbi.nlm.nih.gov/assembly Reference Assembly Basics Oct. 2014: 13 assemblies Oct. 2015: 25 assemblies YRI CEU CEU CHB
- 10. Reference Assembly Basics SangerSanger Illumina Illumina PacBio (older) clone WGS WGS WGS WGS Reads: Method: PacBio (newer) WGS N50: Measure of continuity. Half of the contigs in the assembly are this length or greater.Why all this matters: Longer haplotype blocks Fewer collapsed repeats & segmental duplications Improved annotation More robust mapping target
- 11. Outline • Assembly basics •The assembly model • GRCh38 & updates • Taking advantage of the data
- 12. Sequences from haplotype1 Sequences from haplotype 2 Old Assembly model: compress into a consensus Current Assembly model: represent both haplotypes GRC Assembly Model many
- 13. Assembly (e.g. GRCh38) Primary Assembly Unit Non-nuclear assemblyunit (e.g. MT) PAR Genomic Region (MHC) Genomic Region (UGT2B17) Genomic Region (MAPT) Church et al., PLoS Biol. 2011 Jul;9(7):e1001091 GRC Assembly Model ALT 2 ALT 3 ALT 4 ALT 5 ALT 6 ALT 7 ALT 1
- 14. GRC Assembly Model Altloci alignments are an integral part of the assembly model alignment to chr + scaffold sequence = Alt
- 15. GRCh38 • 178 regionswith alt loci: 2% of chromosome sequence (61.9 Mb) • 261 Alt Loci: 3.6 Mb novel sequence relative to chromosomes • Average alt length = 400 kb, max = ~5 Mb GRCh38
- 16. Outline • Assembly basics •The assembly model • GRCh38 & updates • Taking advantage of the data
- 17. GRCh38: Alt Loci AlignmentLegend no alignmentmismatchdeletion
- 18. chromosome alt/patch reads On-target alignment Off-targetalignments (n=122,922) GRCh38: Alt Loci
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- 21. GRCh38 Base Updates TargetedPCR/WGS: n=91
- 22. GRCh38 Centromeres Miga etal., Genome Res. 2014 Apr;24(4):697-707
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- 25. Assembly (e.g. GRCh38.p1) Primary Assembly Unit Non-nuclear assemblyunit (e.g. MT) ALT 1 ALT 2 ALT 3 ALT 4 ALT 5 ALT 6 ALT 7 PAR Genomic Region (MHC) Genomic Region (UGT2B17) Genomic Region (MAPT) Patches Genomic Region (ABO) Genomic Region (FOXO6) Genomic Region (FCGBP) Assembly Updates Patches FIX NOVEL SCAFFOLD STATUS AT NEXT MAJOR ASSEMBLY RELEASE ALT LOCI -- (integrated) Treat as: Allelic Treat as: Preferred
- 26. GRCh38.p4 • 55 Patches:>400 kb novel sequence • 37 FIX • 18 NOVEL Assembly Updates Learn more about assembly updates at the GRC poster: 1834W (6-7 pm)
- 27. Outline • Assembly basics •The assembly model • GRCh38 & updates • Taking advantage of the data
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- 39. http://www.ncbi.nlm.nih.gov/variation/view/NCBI Variation Viewer Accessingthe Data Learn more about viewing GRCh38 at NCBI: 1748T (12-1 pm)
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- 41. Outline • Assembly basics •The assembly model • GRCh38 & updates • Taking advantage of the data
- 42. GRCh38 Collaborators • NCBIRefSeq and gpipe annotation team • Havana annotators • Karen Miga • David Schwartz • Steve Goldstein • Mario Caceres • Giulio Genovese • Jeff Kidd • Peter Lansdorp • Mark Hills • David Page • Jim Knight • Stephan Schuster • 1000 Genomes GRC SAB • Rick Myers • Granger Sutton • Evan Eichler • Jim Kent • Roderic Guigo • Carol Bult • Derek Stemple • Jan Korbel • Liz Worthey • Matthew Hurles • Richard Gibbs GRC Creditshttp://genomereference.org