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Microscopically-visible abnormalities
~0.4-0.6% of population
-disease risk depends on type of alteration
ATGACTGCGTGTCATG
CCAGGCTAACTGCATG
CTGATCGTACTCGATC
ATGTGGTTAAGTACTC
GTCAATCGCTTGCATA
TGTCTAGTCGCTAGCT
GTACTCGATCGATGCA
CTGATCATTTCCCGAG
CGTATACTGCGTCCAA
N Chr7
Dup Chr7
SNP variants
-100% of population
-percent associated with disease?
Sub-microscopic structural variants
~1kb to 3 Mb deletions, duplications, copy
number variants
-100% of populations
-de novo frequency?
-meiotic and mitotic stability?
-how do they affect gene expression?
-disease risk?
What is content of structural variation in the human genome?
What component of that is involved in disease susceptibility?
Technologies are good for finding >50kb changes
Comparative Genome Hybridisation:
Whole Genome TilePath (WGTP array)
Reference
DNA
Test
DNA
•26,973 large insert clones
•94.4% of euchromatin
Comparative Intensity Analysis:
Affymetrix 500K Early Access SNP chip
Test
DNA 1
Test
DNA 2
Constructing a CNV map of the human genome
-269 Hapmap samples examined
using tiling BAC + Affy 500k
-1448 CNVs
-360 Mb of CNVs in 269 HapMap
samples covering 12%
Of genome
-avg. size 254 kb
-avg. of 111 CNVs per genome
~10-20 Mb CNV per genome
-overlap 2,909 genes
-overlap 286 OMIM genes
Consortium unpublished
Matt Hurles/Nigel Carter (Sanger), Charles Lee (Harvard), Keith Jones (Affymetrix),
Hiro Aburatani (Univ. of Tokyo), Xavier Estivill (Spain), Steve Scherer (Toronto)
The next frontier…
-robust identification of variants in 1-50 kb size
-optical mapping (D. Schwarz)
-paired-end clone mapping (E. Eichler)
-other techniques
-technologies that capture all variation?
-complete sequencing and comparison