High-resolution genomic profiling of chromosomal aberrations using Infinium whole-genome genotyping

DA Peiffer, JM Le, FJ Steemers, W Chang… - Genome …, 2006 - genome.cshlp.org
DA Peiffer, JM Le, FJ Steemers, W Chang, T Jenniges, F Garcia, K Haden, J Li, CA Shaw…
Genome research, 2006genome.cshlp.org
Array-CGH is a powerful tool for the detection of chromosomal aberrations. The introduction
of high-density SNP genotyping technology to genomic profiling, termed SNP-CGH,
represents a further advance, since simultaneous measurement of both signal intensity
variations and changes in allelic composition makes it possible to detect both copy number
changes and copy-neutral loss-of-heterozygosity (LOH) events. We demonstrate the utility of
SNP-CGH with two Infinium whole-genome genotyping BeadChips, assaying 109,000 and …
Array-CGH is a powerful tool for the detection of chromosomal aberrations. The introduction of high-density SNP genotyping technology to genomic profiling, termed SNP-CGH, represents a further advance, since simultaneous measurement of both signal intensity variations and changes in allelic composition makes it possible to detect both copy number changes and copy-neutral loss-of-heterozygosity (LOH) events. We demonstrate the utility of SNP-CGH with two Infinium whole-genome genotyping BeadChips, assaying 109,000 and 317,000 SNP loci, to detect chromosomal aberrations in samples bearing constitutional aberrations as well tumor samples at sub-100 kb effective resolution. Detected aberrations include homozygous deletions, hemizygous deletions, copy-neutral LOH, duplications, and amplifications. The statistical ability to detect common aberrations was modeled by analysis of an X chromosome titration model system, and sensitivity was modeled by titration of gDNA from a tumor cell with that of its paired normal cell line. Analysis was facilitated by using a genome browser that plots log ratios of normalized intensities and allelic ratios along the chromosomes. We developed two modes of SNP-CGH analysis, a single sample and a paired sample mode. The single sample mode computes log intensity ratios and allelic ratios by referencing to canonical genotype clusters generated from ∼120 reference samples, whereas the paired sample mode uses a paired normal reference sample from the same individual. Finally, the two analysis modes are compared and contrasted for their utility in analyzing different types of input gDNA: low input amounts, fragmented gDNA, and Phi29 whole-genome pre-amplified DNA.
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