Human Molecular Genetics Advance Access originally published online on August 28, 2007
Human Molecular Genetics 2007 16(22):2770-2779; doi:10.1093/hmg/ddm234
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Optimal design of oligonucleotide microarrays for measurement of DNA copy-number
1 Department of Genome Sciences, University of Washington School of Medicine, 2 Howard Hughes Medical Institute, 1705 NE Pacific St., Seattle, WA 98195, USA and 3 Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA
* To whom correspondence should be addressed at: Department of Genome Sciences, University of Washington and Howard Hughes Medical Institute, Foege Building S413A, Box 355065, 1705 NE Pacific St., Seattle, WA 98195, USA. Tel: +1 2065439526; Fax: +1 2066857301; Email: 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 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 an 
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 (particularly 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 with 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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