By Mark Wanner
This month Charles Lee, Ph.D., began work as the scientific director at The Jackson Laboratory for Genomic Medicine in Farmington, Conn. Lee is internationally recognized for his discoveries about genomic copy number variations (CNVs), so his arrival at JAX was big news throughout the research community. Most people not working in genetics and genomics, however, probably don’t know what CNVs are and why they are important to health and disease.
What are CNVs?
We all have variations in our genomes that affect how we look, think and act—some even help some people run faster, jump higher or think more abstractly than most of us. Others cause disease or increase susceptibilities.
But say you possessed a near-ideal genome sequence that stacked the odds in favor of longevity and physical and mental wellbeing. That still might not be good enough to escape health problems. While DNA sequences capture most of the clinical genomics attention, scientists have learned over the last decade that something called copy number variations (CNVs) can also play a role in disease.
The simple definition of a CNV is the presence of something other than two copies of a gene in the genome. Inheritance of genes was originally thought to be quite straightforward—each healthy individual has two copies of all their genes, one inherited from mom and the other from dad. What school children learn about Mendel and his peas, such as dominant and recessive inheritance, is based on this simple arithmetic.
CNVs can contribute to disease and other health issues. Surprisingly, recent research has shown that healthy individuals also typically have relatively large sections of DNA, between 1,000 and 5,000,000 bases, added and subtracted from their genomes. When DNA is added (duplications), they may carry three or more copies of the genes in that DNA segment. When it’s subtracted (deletions), they may carry one or even zero copies of a gene. There are apparently hundreds of such variations within most genomes.
When a duplication occurs involving entire chromosomes, it can cause significant developmental disorders, such as trisomy 21, or Down's syndrome. Trisomy 21 means that there are three copies of chromosome 21 instead of the normal two, and while not included in the CNV classification, it demonstrates the effects that can occur when additional gene copies are present on a massive scale. CNVs typically confer more subtle variation, adding up to a large number of small effects.
A brief history
The unexpected abundance of CNVs was not recognized until soon after the reference human genome was completed over a decade ago. That’s when Charles Lee, working at Harvard, encountered difficulty with human genotyping in 2002. Genotype anomalies in patients were expected, but Lee discovered the healthy control group also showed confounding variability in their genomes. In particular, Lee kept finding additional copies of specific genes. This led to a research project in which he set out to measure just how common these additional copies were across the genome. He soon published a paper showing that CNVs are in fact common and occur throughout the human genome.
Since then it has become recognized that CNVs contribute a great deal to human genomic diversity. They may provide as much as three times the amount of DNA variation as the better-known single nucleotide polylmorphisms (SNPs), in which single base pairs vary between individuals without affecting function. Research has also indicated that CNVs can alter gene expression and influence the regulation of genes in their vicinity.
Associating CNVs with disease is an ongoing field of research. It adds yet another challenging twist in the large effort to match genotype with phenotype. That is, how does our genetic material add up to produce all of our traits, including our susceptibilities to disease? Evidence is mounting that CNVs can play significant roles, and a few specific examples have been found.
Interestingly, CNVs have been shown to confer protection from some infectious diseases, including HIV and malaria. Rare CNVs have also been implicated in neurological disorders such as mental retardation, autism and schizophrenia. Overall, however, finding associations between CNVs and disease has seldom been straightforward. While CNVs have been implicated in many other diseases, the specific role or roles they play remains unclear. As with much of genomic research, we are getting a better idea of the general situation, but we are in the early days of understanding how it all fits together.
JAX Genomic Medicine
Lee leads a growing faculty that is launching an impressive slate of research initiatives well in advance of the formal opening of the permanent JAX Genomic Medicine facility. The research effort is already progressing beyond genome sequencing in the search for links between genomics and human disease.
The sequence provides a necessary starting point, but genomes are complex, three-dimensional structures that are far more dynamic than a simple string of DNA base pair letters -- ATCGs -- can convey. JAX Genomic Medicine researchers are investigating organizational, structural and regulatory systems in the human genome. Such genome-wide studies look for factors that influence function throughout the genome and the variations and disruptions that contribute to complex disease, including CNVs.
Of course, bridging the gap between research and clinical delivery is a significant challenge. JAX Genomic Medicine scientists will work closely with clinicians and have access to human patient samples. Combining the clinical interface with the Laboratory’s unmatched experimental model resources and tools provides exciting opportunities for accelerating the path leading from scientific discovery to medical progress.