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Taking Advantage of GRCh38
Valerie Schneider
12 February 2014
Introducing GRCh38

GRCh38: Dec. 24, 2013
Time for change

GRCh37.p13
GRCh38
• 178 Regions: 3.15% of chromosome sequence
• 178 regions with alt loci: 2% of chromoso...
GRCh38: Assembly Stats

http://genomereference.org
GRCh38: Annotation Stats
GRCh38 Sequence Updates
MAF<5%
Mismatch
in
pseudo/pr
txpt
n=1413

Annotator
and clinical
requests
n= ~260

SNV MAF = 0
n=1...
GRCh38 Sequence Updates
Pile-Up Analysis: “Never Seen” Mismatched Bases Originating from RP11 Components

n=10489

79% of ...
GRCh38: Sequence Updates

Coding Consequences
GRCh38 Model Centromeres
Until now, centromeres have been defined as multi-megabase gaps in the assembly
GRCh38 Model Centromeres
Karen Miga (Kent Lab, UCSC)
GRCh38 Model Centromeres

http://genomereference.org
GRCh38 Sequence Addition

1q32

1q21 1p21

Dennis et al., 2012
GRCh38 Path Updates
HYDIN: chr16 (16q22.2)

Doggett et al., 2006

HYDIN2: chr1 (1q21.1)
Missing in NCBI35/NCBI36

Unlocali...
GRCh38: Novel Sequence
GRCh38 Alt Loci
Sequences from haplotype 1
Sequences from haplotype 2

Old Assembly model: compress into a consensus

New ...
GRCh38: Alt Loci
GRCh38: Alt Loci
Part of chr22 assembly
Alternate locus for chr22
Kidd et al., PLoS Genet. (2007) PMID: 17447845

Black: d...
GRCh38: Alt Loci
reads

On-target alignment

alt/patch
Off-target alignments
chromosome

(n=122,922)
GRCh38: Alt Loci
GRCh38: Alt Loci
Masks and alt aware aligners reduce the incidence of
ambiguous alignments observed when aligning reads to...
http://www.ncbi.nlm.nih.gov/genome/tools/remap

ftp://ftp.ncbi.nlm.nih.gov/genbank/genomes/Eukaryotes/
vertebrates_mammals...
GRCh38 Credits

Collaborators

GRC SAB

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NCBI RefSeq and gpipe annotation t...
Schneider_AGBT2014
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Schneider_AGBT2014

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Presentation on the GRCh38 human reference genome assembly from the 2014 AGBT meeting.

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Schneider_AGBT2014

  1. 1. Taking Advantage of GRCh38 Valerie Schneider 12 February 2014
  2. 2. Introducing GRCh38 GRCh38: Dec. 24, 2013
  3. 3. Time for change GRCh37.p13 GRCh38 • 178 Regions: 3.15% of chromosome sequence • 178 regions with alt loci: 2% of chromosome • 131 FIX patches: add 6.8 Mb novel sequence sequence (61.9 Mb) • 73 NOVEL patches: add >800kb novel sequence • 261 Alt Loci: 3.6 Mb novel sequence relative to chromosomes
  4. 4. GRCh38: Assembly Stats http://genomereference.org
  5. 5. GRCh38: Annotation Stats
  6. 6. GRCh38 Sequence Updates MAF<5% Mismatch in pseudo/pr txpt n=1413 Annotator and clinical requests n= ~260 SNV MAF = 0 n=15,244 MAF=0 Insertions n=834 MAF=0 Deletions n=1541
  7. 7. GRCh38 Sequence Updates Pile-Up Analysis: “Never Seen” Mismatched Bases Originating from RP11 Components n=10489 79% of these bases are heterozygous in RP11 WGS
  8. 8. GRCh38: Sequence Updates Coding Consequences
  9. 9. GRCh38 Model Centromeres Until now, centromeres have been defined as multi-megabase gaps in the assembly
  10. 10. GRCh38 Model Centromeres Karen Miga (Kent Lab, UCSC)
  11. 11. GRCh38 Model Centromeres http://genomereference.org
  12. 12. GRCh38 Sequence Addition 1q32 1q21 1p21 Dennis et al., 2012
  13. 13. GRCh38 Path Updates HYDIN: chr16 (16q22.2) Doggett et al., 2006 HYDIN2: chr1 (1q21.1) Missing in NCBI35/NCBI36 Unlocalized in GRCh37 Placed in GRCh38 Alignment of HYDIN2 Genomic, 300 Kb, 99.4% ID Alignment of HYDIN2 Genomic, 300 Kb, 99.4% ID Alignment of HYDIN CHM1_1.0, >99.9% ID Alignment of HYDIN CHM1_1.0, >99.9% ID
  14. 14. GRCh38: Novel Sequence
  15. 15. GRCh38 Alt Loci Sequences from haplotype 1 Sequences from haplotype 2 Old Assembly model: compress into a consensus New Assembly model: represent both haplotypes
  16. 16. GRCh38: Alt Loci
  17. 17. GRCh38: Alt Loci Part of chr22 assembly Alternate locus for chr22 Kidd et al., PLoS Genet. (2007) PMID: 17447845 Black: deletion configuration
  18. 18. GRCh38: Alt Loci reads On-target alignment alt/patch Off-target alignments chromosome (n=122,922)
  19. 19. GRCh38: Alt Loci
  20. 20. GRCh38: Alt Loci Masks and alt aware aligners reduce the incidence of ambiguous alignments observed when aligning reads to the full assembly Mask1: mask chr for fix patches, scaffold for novel/alts. Mask2: mask only on scaffolds
  21. 21. http://www.ncbi.nlm.nih.gov/genome/tools/remap ftp://ftp.ncbi.nlm.nih.gov/genbank/genomes/Eukaryotes/ vertebrates_mammals/Homo_sapiens/GRCh38
  22. 22. GRCh38 Credits Collaborators GRC SAB • • • • • • • • • • • • • • • • • • • • • • • NCBI RefSeq 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 Rick Myers Granger Sutton Evan Eichler Jim Kent Roderic Guigo Carol Bult Derek Stemple Matthew Hurles Richard Gibbs

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