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Human Molecular Genetics Advance Access published online on August 28, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm234
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Optimal design of oligonucleotide microarrays for measurement of DNA copy number

Andrew J. Sharp1, Andy Itsara1, Ze Cheng1,2, Can Alkan1, Stuart Schwartz3 and Evan E. Eichler1,2,{dagger}

1 Department of Genome Sciences, University of Washington School of Medicine, 1705 NE Pacific St. Seattle, WA, 98195, USA 2 Howard Hughes Medical Institute 3 Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA

{dagger} Corresponding author: Evan Eichler, Ph.D., Department of Genome Sciences, University of Washington and Howard Hughes Medical Institute, Foege Building S413A, Box 355065, 1705 NE Pacific St., Seattle, WA 98195, Telephone: (206) 543-9526, Fax: (206) 685-7301, E-mail: eee{at}gs.washington.edu

Received June 18, 2007; Revised August 17, 2007; Accepted August 17, 2007

Copy-number variants (CNVs) occur frequently within the human genome, and may be associated with many human phenotypes. If disease association studies of CNVs are to be performed routinely, it is essential that the copy-number status can be accurately genotyped. We systematically assessed the dynamic range response of an oligonucleotide microarray platform to accurately predict copy number in a set of seven patients who had previously been shown to carry between 1 and 6 copies of a ~4 Mb region of 15q12.2-q13.1. We identify probe uniqueness, probe length, uniformity of probe melting temperature, overlap with SNPs and common repeats (paticularly Alu elements), and guanine homopolymer content as parameters that significantly affect probe performance. Further, we prove the influence of these criteria on array performance by using these parameters to prospectively filter data from a second array design covering an independent genomic region and observing significant improvements in data quality. The informed selection of probes which have superior performance characteristics allows the prospective design of oligonucleotide arrays which show increased sensitivity and specificity compared to current designs. Although based on the analysis of data from comparative genomic hybridization experiments, we anticipate that our results are relevant to the design of improved oligonucleotide arrays for high-throughput copy-number genotyping of complex regions of the human genome


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