A002
MEASUREMENT OF DNA SEQUENCE COPY NUMBER VARIATION IN HUMAN DISEASE
USING COMPARATIVE GENOMIC HYBRIDIZATION TO MICROARRAYS
Albertson DG 1, Segraves R 1, Zhang XX 1,2, Palmer J 1,
Blackwood S 1, Hamilton G 1, Dairkee S 3, Ljung B 1, Bolund L 4,
Yuang H 4, Niebuhr E 2, Gray JW 1, Pinkel D 1
1 University of California, San Francisco, San Francisco CA,
2 Medical Genetics, University of Copenhagen, Denmark,
3 Geraldine Brush Cancer Research Institute, San Francisco CA,
4 Inst. of Human Genetics, Aarhus University, Aarhus, Denmark
Comparative genomic hybridization (CGH) has proven to be an effective
method for detecting and mapping genetic alterations that are due to
changes in DNA sequence copy number. The use of metaphase chromosomes
as the hybridization target has previously limited the resolution of
CGH to 10-20 Mb. However, we have now implemented a new form of high
resolution CGH by replacing the normal metaphase spread with an array
of genomic cosmid, P1, and BAC clones. This approach provides a resolution
at least a factor of 100 better than standard CGH, as it is determined
only by the size and spacing of the target genomic clones. We have applied
array CGH to measure variation in DNA sequence copy number occurring in
breast cancer and to map the extent of deletions on chromosome 5p in Cri
du Chat patients. In addition, the unprecedented high dynamic range and
quantitative accuracy of array CGH provide for the first time, the capability
to very precisely map copy number profiles across an amplified region for
which contiguous and overlapping clones are available as the array target
elements. In some tumors, copy number profiles show narrow peaks of
amplification. This information focuses attention on the genes mapping
to the peak region and may aid in the identification of the candidate
driver oncogenes. These initial 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.