Genome Representation and Variant Identification

Deanna M. Church

ISCA Consortium Conference

From Green ED et al. Nature 2011

http://www.ncbi.nlm.nih.gov/variation/tools/1000genomes

CEPH: A=1.000 G=0

YRI: A=0.5852 G=0.4148

Multiple submissions

FrequencyData

1000G

Suspect

Sudmant et al., 2010

Kidd et al, 2007 APOBEC cluster

BLACK: DeletionWhite: Insertion

http://www.ncbi.nlm.nih.gov/dbvar

Variant Call Ambiguitystart stop

Inner start Inner stop

Outer start Outer stop

Probes with decreased signal intensityProbes with expected signal intensity

breakpoint breakpoint

Inner start Inner stop

Variant Call AmbiguityOuter start Outer stop

Fosmid clone (40 Kb +/- 1 Kb)

20Kb Clone has an insertionrelative to the genome

Clone has a deletionrelative to the genome 60 Kb

Large-Scale Variation Complicates Genome Assembly

Sequences from haplotype 1Sequences from haplotype 2

Old Assembly model: compress into a consensus

New Assembly model: represent both haplotypes

MHC (chr6)Chr 6 representation (PGF)

Alt_Ref_Locus_2 (COX)

Church et al., 2011 PLoS Biology

http://genomereference.org

GRCh37 (hg19)

http://genomereference.org

7 alternate haplotypesat the MHC

Alternate loci released as:FASTA

AGPAlignment to chromosome

UGT2B17 MHC MAPT

Richa AgarwalaEugene Yaschenko

70 Fix PATCHES: Chromosome will update in GRCh3871 Novel PATCHES: Additional sequence added

Releasing patches quarterly

Summer of 2013

GRCh37 chr17

GRCh37 Myo19 Fix Patch

Dennis et al., 2012

1q32 1q21 1p21

1p21 patch alignment to chromosome 1

Thanks!

For Slides: Evan Eichler

The Genome Reference ConsortiumThe Genome Center at Washington University The Wellcome Trust Sanger InstituteThe European Bioinformatics InstituteThe National Center for Biotechnology Information

Church group at NCBIValerie SchneiderNathan BoukHsiu-Chuan ChenPeter MericVictor AnanievChao ChenJohn LopezJohn GarnerTim HefferonCliff Clausen NCBI

Alt-Aware Alignments: Richa Agarwala Eugene Yaschenko Chunlin Xiao Steve Sherry

1000 Genome browser: Doug Slotta Eugene Yaschenko Victor Ananiev Lon Phan Steve Sherry Rob Cohen Deanna Church