title: Improved detection of global copy number variation using high density, non-polymorphic oligonucleotide probes.
abstract: BACKGROUND
  DNA sequence diversity within the human genome may be more greatly affected by copy number variations (CNVs) than single nucleotide polymorphisms (SNPs). Although the importance of CNVs in genome wide association studies (GWAS) is becoming widely accepted, the optimal methods for identifying these variants are still under evaluation. We have previously reported a comprehensive view of CNVs in the HapMap DNA collection using high density 500 K EA (Early Access) SNP genotyping arrays which revealed greater than 1,000 CNVs ranging in size from 1 kb to over 3 Mb. Although the arrays used most commonly for GWAS predominantly interrogate SNPs, CNV identification and detection does not necessarily require the use of DNA probes centered on polymorphic nucleotides and may even be hindered by the dependence on a successful SNP genotyping assay.
  
  
  RESULTS
  In this study, we have designed and evaluated a high density array predicated on the use of non-polymorphic oligonucleotide probes for CNV detection. This approach effectively uncouples copy number detection from SNP genotyping and thus has the potential to significantly improve probe coverage for genome-wide CNV identification. This array, in conjunction with PCR-based, complexity-reduced DNA target, queries over 1.3 M independent NspI restriction enzyme fragments in the 200 bp to 1100 bp size range, which is a several fold increase in marker density as compared to the 500 K EA array. In addition, a novel algorithm was developed and validated to extract CNV regions and boundaries.
  
  
  CONCLUSIONS
  Using a well-characterized pair of DNA samples, close to 200 CNVs were identified, of which nearly 50% appear novel yet were independently validated using quantitative PCR. The results indicate that non-polymorphic probes provide a robust approach for CNV identification, and the increasing precision of CNV boundary delineation should allow a more complete analysis of their genomic organization.
authors: Affymetrix, Inc, 3420 Central Expressway; Santa Clara, CA 95051, USA. fan_shen@affymetrix.com
authors: Fan
authors: F
authors: Shen
authors: Jing
authors: J
authors: Huang
authors: Karen R
authors: KR
authors: Fitch
authors: Vivi B
authors: VB
authors: Truong
authors: Andrew
authors: A
authors: Kirby
authors: Wenwei
authors: W
authors: Chen
authors: Jane
authors: J
authors: Zhang
authors: Guoying
authors: G
authors: Liu
authors: Steven A
authors: SA
authors: McCarroll
authors: Keith W
authors: KW
authors: Jones
authors: Michael H
authors: MH
authors: Shapero
mesh_terms: D018628:Gene Dosage; D014644:Genetic Variation; D015894:Genome, Human / Q000235:genetics*; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D015345:Oligonucleotide Probes; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide
chemical_list: D015345:Oligonucleotide Probes