Systematic assessment of copy number variant detection via genome-wide SNP genotyping.
SNP genotyping has emerged as a technology to incorporate copy number variants (CNVs) into genetic analyses of human traits. However, the extent to which SNP platforms accurately capture CNVs remains unclear. Using independent, sequence-based CNV maps, we find that commonly used SNP platforms have limited or no probe coverage for a large fraction of CNVs. Despite this, in 9 samples we inferred 368 CNVs using Illumina SNP genotyping data and experimentally validated over two-thirds of these. We also developed a method (SNP-Conditional Mixture Modeling, SCIMM) to robustly genotype deletions using as few as two SNP probes. We find that HapMap SNPs are strongly correlated with 82% of common deletions, but the newest SNP platforms effectively tag about 50%. We conclude that currently available genome-wide SNP assays can capture CNVs accurately, but improvements in array designs, particularly in duplicated sequences, are necessary to facilitate more comprehensive analyses of genomic variation.
Cooper
Gregory M
GM
Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA. coopergm@u.washington.edu
Zerr
Troy
T
Kidd
Jeffrey M
JM
Eichler
Evan E
EE
Nickerson
Deborah A
DA
D002648:Child; D002877:Chromosomes, Human / Q000235:genetics*; D004247:DNA / Q000235:genetics*; D005260:Female; D005784:Gene Amplification; D017353:Gene Deletion; D018628:Gene Dosage / Q000235:genetics*; D014644:Genetic Variation; D015894:Genome, Human; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D044382:Population Groups / Q000235:genetics*
D004247:DNA
PLoS Genet. 2007 Oct;3(10):1787-99
17953491
Nucleic Acids Res. 2007;35(6):2013-25
17341461
Nat Genet. 2005 Jul;37(7):727-32
15895083
Nat Genet. 2007 Oct;39(10):1256-60
17828263
Nature. 2004 Oct 21;431(7011):927-30
15496912
Annu Rev Genet. 2000;34:297-329
11092830
Science. 2005 Mar 4;307(5714):1434-40
15637236
Science. 2008 Apr 25;320(5875):539-43
18369103
Nature. 2005 Oct 27;437(7063):1299-320
16255080
Science. 2004 Jul 23;305(5683):525-8
15273396
Nature. 2008 May 1;453(7191):56-64
18451855
Hum Mol Genet. 2007 Dec 1;16(23):2783-94
17666407
Nat Genet. 2006 Sep;38(9):1038-42
16906162
Nature. 2007 Jun 7;447(7145):661-78
17554300
Science. 2007 Oct 19;318(5849):420-6
17901297
Nature. 2007 May 10;447(7141):161-5
17495918
Nat Genet. 2006 Jan;38(1):75-81
16327808
Nature. 2006 Nov 23;444(7118):444-54
17122850
Science. 2003 Oct 31;302(5646):841
14593171
Genome Res. 2006 Sep;16(9):1136-48
16899659
Bioinformatics. 2007 Jun 1;23(11):1424-6
17384021
Nat Genet. 2006 Jan;38(1):86-92
16468122
Am J Hum Genet. 2006 Aug;79(2):275-90
16826518
Nat Genet. 2007 Jul;39(7 Suppl):S22-9
17597777
Hum Mol Genet. 2006 Apr 1;15(7):1159-67
16497726
Genome Res. 2006 Dec;16(12):1575-84
17122084
Am J Hum Genet. 2005 Jul;77(1):78-88
15918152
Genome Res. 2007 Nov;17(11):1665-74
17921354