Until recently, single nucleotide polymorphisms (SNPs) were thought to represent the only source of inter-individual variation at the genome level. Subsequently, it became apparent that different individuals may harbor various copy numbers of certain genes or genomic regions.
This newly unveiled source of genetic variability, which became known as copy number variation (CNV), is believed to involve more nucleotides than all SNPs combined. Such extensive inter-individual genetic variation reveals that human genomes are more dissimilar than initially thought, and even raised the question about whether it is still meaningful to talk about a single reference human genome.
“Copy number variations, in addition to DNA mutations assayed by sequencing, are probably the most reliable data in understanding what is involved in tumor formation, and are key for evaluating potential therapeutic targets,” notes Gregory J. Riggins, M.D., Ph.D., professor of neurosurgery and oncology at the Johns Hopkins Medical Institute.
At next month’s CHI conference, “Comprehending Copy Number Variation”, Dr. Riggins will talk about a genome-wide CNV analysis that he and colleagues conducted to investigate the genomic changes in glioblastoma multiforme. This malignant brain tumor was previously shown to be frequently associated with copy number alterations, either as losses or gains of various chromosomal regions.
By using digital karyotyping and Illumina bead arrays, the scientists found that a locus on the large arm of chromosome 12, which contains the GLI1 and CDK4 oncogenes, is amplified in 33% of the patients. Learning about the genes amplified or deleted by CNVs can provide significant clues about the pathogenic mechanisms involved in tumor formation or progression.
“Since the alterations are in the DNA and easy to decipher, it is relatively easy to do genome-wide assays, and this has become a valuable means for assessing gene alterations in large numbers of tumors,” says Dr. Riggins.
In addition to confirming that different techniques used to survey CNVs lead to similar results, Dr. Riggins and colleagues also established a large collection of copy number changes for this brain disease, which will provide a framework for future studies aiming to design therapies based on molecular targets.