title: Genome-wide detection of human copy number variations using high-density DNA oligonucleotide arrays.
abstract: Recent reports indicate that copy number variations (CNVs) within the human genome contribute to nucleotide diversity to a larger extent than single nucleotide polymorphisms (SNPs). In addition, the contribution of CNVs to human disease susceptibility may be greater than previously expected, although a complete understanding of the phenotypic consequences of CNVs is incomplete. We have recently reported a comprehensive view of CNVs among 270 HapMap samples using high-density SNP genotyping arrays and BAC array CGH. In this report, we describe a novel algorithm using Affymetrix GeneChip Human Mapping 500K Early Access (500K EA) arrays that identified 1203 CNVs ranging in size from 960 bp to 3.4 Mb. The algorithm consists of three steps: (1) Intensity pre-processing to improve the resolution between pairwise comparisons by directly estimating the allele-specific affinity as well as to reduce signal noise by incorporating probe and target sequence characteristics via an improved version of the Genomic Imbalance Map (GIM) algorithm; (2) CNV extraction using an adapted SW-ARRAY procedure to automatically and robustly detect candidate CNV regions; and (3) copy number inference in which all pairwise comparisons are summarized to more precisely define CNV boundaries and accurately estimate CNV copy number. Independent testing of a subset of CNVs by quantitative PCR and mass spectrometry demonstrated a >90% verification rate. The use of high-resolution oligonucleotide arrays relative to other methods may allow more precise boundary information to be extracted, thereby enabling a more accurate analysis of the relationship between CNVs and other genomic features.
authors.affiliation: Research Center for Advanced Science and Technology, The University of Tokyo, Meguro, Tokyo 153-8904, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Komura
authors.forename: Fan
authors.initials: F
authors.lastname: Shen
authors.forename: Shumpei
authors.initials: S
authors.lastname: Ishikawa
authors.forename: Karen R
authors.initials: KR
authors.lastname: Fitch
authors.forename: Wenwei
authors.initials: W
authors.lastname: Chen
authors.forename: Jane
authors.initials: J
authors.lastname: Zhang
authors.forename: Guoying
authors.initials: G
authors.lastname: Liu
authors.forename: Sigeo
authors.initials: S
authors.lastname: Ihara
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nakamura
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Hurles
authors.forename: Charles
authors.initials: C
authors.lastname: Lee
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Scherer
authors.forename: Keith W
authors.initials: KW
authors.lastname: Jones
authors.forename: Michael H
authors.initials: MH
authors.lastname: Shapero
authors.forename: Jing
authors.initials: J
authors.lastname: Huang
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Aburatani
mesh_terms: D000465:Algorithms; D000483:Alleles; D002877:Chromosomes, Human; D004247:DNA / Q000235:genetics*; D017353:Gene Deletion; D018628:Gene Dosage; D014644:Genetic Variation; D015894:Genome, Human; D006720:Homozygote; D006801:Humans; D013058:Mass Spectrometry; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide
chemical_list: D004247:DNA