While anomalous structural changes have been observed in genes stretching back to the early 20th century, the modern concept of a copy number variant originated in the early 2000s.
As we mentioned before, most researchers until this time had seen genomic variation in humans through the lens of SNPs. But researchers like Charles Lee (currently with the Jackson Laboratory for Genomic Medicine), Michael Wigler (Cold Spring Harbor), and Stephen Scherer (Hospital for Sick Children, Toronto) were among the first to notice and document more genomic variation in the form of copy number variants.
As exhaustively laid out by Ingrid Lobo in a 2008 article published in Nature Education, it was Charles Lee who, in 2002, following a series of unsuccessful attempts to genotype patients, appears to have been the first to document observations “that healthy control patients showed major variations in their genetic sequences, with some having more copies of specific genes than others.” Lee then collaborated with Steven Scherer, “who had made similar observations, and together their labs used array-based comparative genomic hybridization approaches to measure the occurrence of these copy variants across the genome.”2
“Meanwhile,” Lobo explains, “Michael Wigler was also observing differences in copy numbers in healthy individuals using a complementary microarray technique involving representational oligonucleotide probes to detect amplifications and deletions in the genome.”
In 2004, these researchers published findings that “indicated large-scale variations in copy number were common and occurred in hundreds of places in the human genome, including areas coding for disease-related genes.”
BioDiscovery’s own VP of Sales, Dan Clutter, Ph.D., was fortunate enough to be on the frontline of CNV discovery at this time—helping equip researchers with microarray technologies that facilitated many of the initial studies into these variations.
“Back then, when you looked at the genome at a molecular level, you expected to see two copies of every gene. But we started seeing variations in genes. At the time, most people talked about SNPs and changes in individual nucleotides.
When we saw changes in copy number, we were really surprised. And when we looked at cancer samples, we saw that variations were everywhere. Where you’d expect to see two copies of every gene, you were actually seeing giant pieces of DNA moving, disappearing, and amplifying. Then we came across labs doing treatments of various cancers with chemicals, compounds, anti-cancer compounds, and we would see the genome start to become normal again. It was astonishing.
In the early days of CV research, this was all done in cell cultures. It was a long time before we started sequencing human tumors to understand what was going on at a genomic level. Now, we’re doing single-cell sequencing, looking at a whole tumor and sequencing thousands of cells from that tumor. Some cells aren't that disturbed. Others are. The evolution of CNV research has been truly fascinating.”
— Dan Clutter, VP of Sales, BioDiscovery
It would be roughly a decade from its discovery before CNV detection and analysis would be meaningfully applied in a clinical setting. During this time and since, thousands of publications marked a slow-moving explosion in our understanding of CNVs as researchers reveal more about their functions in human biology and usefulness in the clinic.
Below, we’ve excerpted a portion of the historical timeline presented in a recent review published in Biomedical Journal outlining the major milestones in CNV discovery and research. We’ve also compiled a few of the publications that mark these milestones through time.