Comparative genomic hybridization using arrays of genomic cosmid, P1 and BAC clones (array CGH) provides quantitative copy number data over a wide dynamic range with resolution determined solely by the size and genomic spacing of the arrayed clones. We have demonstrated previously that array CGH has the measurement precision to reliably discriminate single copy-level changes from diploid in the human genome. We are currently using this capability to map the extent of deletions on chromosome 5p in Cri du Chat patients and find fluorescence ratios for diploid targets of 1.0±0.07, while ratios on deleted clones are 0.55±0.05 (mean±s.d.). This measurement precision is expected to permit recognition of deletions with false-positive and -negative rates below one in several thousand. Recently, we have developed procedures that adequately suppress hybridization from repeat sequences in mouse genomes so that heterozygous deletions and duplications can now be mapped with the same accuracy in interspecific backcross animals. In the course of these studies, one clone in mouse and one in human were found to have a ratio of approximately 0.75 when included in the deletion. FISH mapping showed that these clones hybridized to two locations in the genome. Thus, the measured ratios on these clones reflect the accurate measurement of the copy number decrease from 4 to 3 copies in the deletions.

The unprecedented high dynamic range and quantitative accuracy of array CGH also provide the capability to very precisely map copy number profiles across an amplified region using contiguous and overlapping clones as the array elements. When such an analysis was performed across a 1-Mb contig at 20q13.2, we observed a constant level of elevated copy number across the region in some tumours, whereas we recorded abrupt variations in copy number in others. The boundaries of different levels of amplification were thus mapped to within a fraction of a BAC or P1 clone. In some tumours, copy number profiles showed narrow peaks of amplification (some as small as ∼300 kb) and revealed the presence of two separate regions in the 1-Mb contig that could be the most highly amplified in different tumours. This information focuses attention on the genes mapping to the peak regions and may aid in the identification of the candidate driver oncogenes. These studies using array CGH illustrate the capability of this technology for scanning the entire genome for copy number aberrations, identifying disease genes and providing diagnostic information.