A robust algorithm for copy number detection using high-density oligonucleotide single nucleotide polymorphism genotyping arrays.

We have developed a robust algorithm for copy number analysis of the human genome using high-density oligonucleotide microarrays containing 116,204 single-nucleotide polymorphisms. The advantages of this algorithm include the improvement of signal-to-noise (S/N) ratios and the use of an optimized reference. The raw S/N ratios were improved by accounting for the length and GC content of the PCR products using quadratic regressions. The use of constitutional DNA, when available, gives the lowest SD values (0.16 +/- 0.03) and also enables allele-based copy number detection in cancer genomes, which can unmask otherwise concealed allelic imbalances. In the absence of constitutional DNA, optimized selection of multiple normal references with the highest S/N ratios, in combination with the data regressions, dramatically improves SD values from 0.67 +/- 0.12 to 0.18 +/- 0.03. These improvements allow for highly reliable comparison of data across different experimental conditions, detection of allele-based copy number changes, and more accurate estimations of the range and magnitude of copy number aberrations. This algorithm has been implemented in a software package called Copy Number Analyzer for Affymetrix GeneChip Mapping 100K arrays (CNAG). Overall, these enhancements make CNAG a useful tool for high-resolution detection of copy number alterations which can help in the understanding of the pathogenesis of cancers and other diseases as well as in exploring the complexities of the human genome.

[1]  S. P. Fodor,et al.  Light-directed, spatially addressable parallel chemical synthesis. , 1991, Science.

[2]  F. Rüschendorf,et al.  Molecular karyotyping using an SNP array for genomewide genotyping , 2004, Journal of Medical Genetics.

[3]  Luc Girard,et al.  An integrated view of copy number and allelic alterations in the cancer genome using single nucleotide polymorphism arrays. , 2004, Cancer research.

[4]  Kenny Q. Ye,et al.  Large-Scale Copy Number Polymorphism in the Human Genome , 2004, Science.

[5]  M. Shapero,et al.  High-resolution analysis of DNA copy number using oligonucleotide microarrays. , 2004, Genome research.

[6]  Bradley P. Coe,et al.  A tiling resolution DNA microarray with complete coverage of the human genome , 2004, Nature Genetics.

[7]  J. Bennett.  The Leukemia-Lymphoma Cell Line Facts Book , 2002 .

[8]  Shen Hu,et al.  Detection of DNA copy number abnormality by microarray expression analysis , 2004, Human Genetics.

[9]  C. Lengauer,et al.  Aneuploidy and cancer , 2004, Nature.

[10]  S. P. Fodor,et al.  Large-scale genotyping of complex DNA , 2003, Nature Biotechnology.

[11]  Christian A. Rees,et al.  Microarray analysis reveals a major direct role of DNA copy number alteration in the transcriptional program of human breast tumors , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[12]  Cheng Li,et al.  dChipSNP: significance curve and clustering of SNP-array-based loss-of-heterozygosity data , 2004, Bioinform..

[13]  S. P. Fodor,et al.  Genotyping over 100,000 SNPs on a pair of oligonucleotide arrays , 2004, Nature Methods.

[14]  L. Feuk,et al.  Detection of large-scale variation in the human genome , 2004, Nature Genetics.

[15]  David C Christiani,et al.  High-resolution single-nucleotide polymorphism array and clustering analysis of loss of heterozygosity in human lung cancer cell lines , 2004, Oncogene.

[16]  B. Ylstra,et al.  High resolution microarray comparative genomic hybridisation analysis using spotted oligonucleotides , 2004, Journal of Clinical Pathology.

[17]  Cheng Li,et al.  Genome-wide loss of heterozygosity analysis from laser capture microdissected prostate cancer using single nucleotide polymorphic allele (SNP) arrays and a novel bioinformatics platform dChipSNP. , 2003, Cancer research.

[18]  D. Pinkel,et al.  Comparative Genomic Hybridization for Molecular Cytogenetic Analysis of Solid Tumors , 2022 .

[19]  Keith W. Jones,et al.  Whole genome DNA copy number changes identified by high density oligonucleotide arrays , 2004, Human Genomics.

[20]  T. Lister,et al.  Genome-wide single nucleotide polymorphism analysis reveals frequent partial uniparental disomy due to somatic recombination in acute myeloid leukemias. , 2005, Cancer research.

[21]  W. Kuo,et al.  Quantitative mapping of amplicon structure by array CGH identifies CYP24 as a candidate oncogene , 2000, Nature Genetics.

[22]  S. P. Fodor,et al.  Light-generated oligonucleotide arrays for rapid DNA sequence analysis. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[23]  Tsz-Kwong Man,et al.  Allelic imbalance analysis by high-density single-nucleotide polymorphic allele (SNP) array with whole genome amplified DNA. , 2004, Nucleic acids research.