Integrated detection and population-genetic analysis of SNPs and copy number variation.
Dissecting the genetic basis of disease risk requires measuring all forms of genetic variation, including SNPs and copy number variants (CNVs), and is enabled by accurate maps of their locations, frequencies and population-genetic properties. We designed a hybrid genotyping array (Affymetrix SNP 6.0) to simultaneously measure 906,600 SNPs and copy number at 1.8 million genomic locations. By characterizing 270 HapMap samples, we developed a map of human CNV (at 2-kb breakpoint resolution) informed by integer genotypes for 1,320 copy number polymorphisms (CNPs) that segregate at an allele frequency >1%. More than 80% of the sequence in previously reported CNV regions fell outside our estimated CNV boundaries, indicating that large (>100 kb) CNVs affect much less of the genome than initially reported. Approximately 80% of observed copy number differences between pairs of individuals were due to common CNPs with an allele frequency >5%, and more than 99% derived from inheritance rather than new mutation. Most common, diallelic CNPs were in strong linkage disequilibrium with SNPs, and most low-frequency CNVs segregated on specific SNP haplotypes.
McCarroll
Steven A
SA
Program in Medical and Population Genetics and Genetic Analysis Platform, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
Kuruvilla
Finny G
FG
Korn
Joshua M
JM
Cawley
Simon
S
Nemesh
James
J
Wysoker
Alec
A
Shapero
Michael H
MH
de Bakker
Paul I W
PI
Maller
Julian B
JB
Kirby
Andrew
A
Elliott
Amanda L
AL
Parkin
Melissa
M
Hubbell
Earl
E
Webster
Teresa
T
Mei
Rui
R
Veitch
James
J
Collins
Patrick J
PJ
Handsaker
Robert
R
Lincoln
Steve
S
Nizzari
Marcia
M
Blume
John
J
Jones
Keith W
KW
Rava
Rich
R
Daly
Mark J
MJ
Gabriel
Stacey B
SB
Altshuler
David
D
D002877:Chromosomes, Human / Q000235:genetics*; D004247:DNA / Q000235:genetics*; D018628:Gene Dosage / Q000235:genetics*; D014644:Genetic Variation; D015894:Genome, Human; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D044382:Population Groups / Q000235:genetics*
D004247:DNA