Adjustment of genomic waves in signal intensities from whole-genome SNP genotyping platforms

Whole-genome microarrays with large-insert clones designed to determine DNA copy number often show variation in hybridization intensity that is related to the genomic position of the clones. We found these 'genomic waves' to be present in Illumina and Affymetrix SNP genotyping arrays, con- firming that they are not platform-specific. The causes of genomic waves are not well-understood, and they may prevent accurate inference of copy number variations (CNVs). By measuring DNA con- centration for 1444 samples and by genotyping the same sample multiple times with varying DNA quan- tity, we demonstrated that DNA quantity correlates with the magnitude of waves. We further showed that wavy signal patterns correlate best with GC content, among multiple genomic features consid- ered. To measure the magnitude of waves, we pro- posed a GC-wave factor (GCWF) measure, which is a reliable predictor of DNA quantity (correlation coefficient=0.994 based on samples with serial dilu- tion). Finally, we developed a computational app- roach by fitting regression models with GC content included as a predictor variable, and we show that this approach improves the accuracy of CNV detec- tion. With the wide application of whole-genome SNP genotyping techniques, our wave adjustment method will be important for taking full advantage of genotyped samples for CNV analysis.