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

Abstract

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, confirming 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 concentration for 1444 samples and by genotyping the same sample multiple times with varying DNA quantity, 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 considered. To measure the magnitude of waves, we proposed a GC-wave factor (GCWF) measure, which is a reliable predictor of DNA quantity (correlation coefficient = 0.994 based on samples with serial dilution). Finally, we developed a computational approach by fitting regression models with GC content included as a predictor variable, and we show that this approach improves the accuracy of CNV detection. 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.

Genome-wide detection of copy-number variations in local cattle breeds

“…The following options in CNAM were chosen: univariate outlier removal, maximum number of 100 segments per 10 000 markers, minimum markers per Segment 3, 2000 permutations per pair with a P-value cutoff of 0.005. Individuals that had À0.05 > waviness factor > 0.05 were also excluded, as suggested by Diskin et al (2008).…”

Association between Mitochondrial DNA Copy Number in Peripheral Blood and Incident CKD in the Atherosclerosis Risk in Communities Study

“…Because sequence similarity between mitochondrial and nuclear DNA can adversely affect the accuracy of mtDNA copy number estimates, 39 we curated 25 high-quality mitochondrial SNPs having probes with a perfect match to the annotated mitochondrial location. We used the median of the normalized intensity (log R ratio) for homozygous calls of these 25 mitochondrial SNPs corrected for GC content 40 as the initial estimate of mtDNA copy number. To correct for batch effects, DNA quality, and starting DNA quantity, we generated principal components using the normalized probe intensities of 43,316 autosomal SNPs.…”

Copy number variation in patients with cervical artery dissection

“…On the basis of this preliminary exploration, we identified seven patients with outlier numbers of markers with CN-state a2, as well as with prominent genomic waves. 14 In a second step we filtered the control cohort in a more stringent way and selected four hundred three data sets of high quality (genotyping call rates Z98.0% and the absence of strong genomic waves) from the 1262 PopGen subjects.…”