What is copy number variation? – TCAG

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What is copy number variation?
The human genome is comprised of 6 billion chemical bases (or nucleotides) of DNA packaged into two
sets of 23 chromosomes, one set inherited from each parent. The DNA encodes 30,000 genes. It was
generally thought that genes were almost always present in two copies in a genome. However, recent
discoveries have revealed that large segments of DNA, ranging in size from thousands to millions of DNA
bases, can vary in copy-number. Such copy number variations (or CNVs) can encompass genes leading to
dosage imbalances. For example, genes that were thought to always occur in two copies per genome have
now been found to sometimes be present in one, three, or more than three copies. In a few rare instances
the genes are missing altogether (see figure below). The new findings indicate that our DNA is less than
99.9% identical, as was previously thought.

Why are CNVs important?
Differences in the DNA sequence of our genomes contribute to our uniqueness. These changes influence
most traits including susceptibility to disease. It was thought that single nucleotide changes (called SNPs)
in DNA were the most prevalent and important form of genetic variation. The current studies reveal that
CNVs comprise at least three times the total nucleotide content of SNPs. Since CNVs often encompass
genes, they may have important roles both in human disease and drug response. Understanding the
mechanisms of CNV formation may also help us better understand human genome evolution.

How does the new CNV map help?
The new global CNV map will transform medical
research in four areas. The first and most important
area is in hunting for genes underlying common
diseases. To date, attempts to identify these genes
have not considered the role CNVs may play in human
health. Second, the CNV map is being used to study
familial genetic conditions. Third, there are thousands
of severe developmental defects caused by
chromosomal rearrangements. The CNV map is being
used to exclude variation found in unaffected
individuals, helping researchers to target the region that
might be involved. The data generated will also
contribute to a more accurate and complete human
genome reference sequence used by all biomedical
scientists.

What are the most surprising observations from the
recent papers?
It was startling to discover that 12% of the human
genome was copy number variable in the 270 DNA
samples tested. About 2900 genes, or 10% of those
known, are encompassed by these CNVs. Some CNVs
found in the general population can be millions of
bases in size, affecting numerous genes, yet they have
no observable consequence.

How many CNVs are there in the human genome
and how big are they?
To date, approximately 2000 CNVs have been
described and 1447 of them are from the current study.
There could be thousands more CNVs in the human
population. About 100 CNVs were detected in each
genome examined with the average size being 250,000
bases (an average gene is 60,000 bases). Additional
CNVs will be discovered as technologies for detection
improve and more DNA samples from worldwide
populations are examined.

Can CNVs cause disease?
Most CNVs are benign variants that will not directly cause disease. However, there are several instances
where CNVs that affect critical developmental genes do cause disease. For example, recent reviews have
listed 17 conditions of the nervous system alone – including Parkinson’s Disease and Alzheimer’s Disease
– that can result from copy number variation. To increase the value of the data, the Hospital for Sick
Children has established the ‘Database of Genomic Variants’ to house CNVs found in the general
population. The Wellcome Trust Sanger Institute has developed a database of CNVs (called DECIPHER)
associated with clinical conditions.

What types of genes are found to be copy number variable?
Genes that are involved in the immune system and in brain development and activity – two functions that
have evolved rapidly in humans – tend to be enriched in CNVs. By contrast, genes that play a role in early
development and some genes involved in cell division – both critical to fundamental biology – tend to be
spared.

Are there any bioethical considerations that are unique to CNVs?
Since the discovery of CNVs is so new, bioethics studies are just now underway. Compared to other
genetic variants, CNVs are larger in size and can often involve complex repetitive DNA sequences. They
can also encompass entire genes, many of which have a specific function ascribed to them. For these
reasons CNV data could potentially be more amenable to misinterpretation. Some CNVs could be
employed to add discrimination power in forensics, but typing them is usually less efficient than other types
of genetic markers.

Are there population specific CNVs?
As with all types of genetic variation, CNVs can vary in frequency and occurrence between populations
telling us something of our shared history. As a result of our recent common origin, the vast majority of
copy-number variation – around 89% – is shared among the diverse human populations studied.
Nevertheless, the pattern of CNV that each of us inherits subtly reflects our ancestry and can be used to
infer in which continental population our recent background lies. Striking differences in regions of our
genome between different populations might define variants that have allowed different groups to adapt to
their different environments. One example is the strikingly increased copy number of the HIV-related
CCL3L1 gene in African populations. An understanding of how genetic variation is distributed among
populations not only tells us about human prehistory, but also improves our ability to find disease genes.
Yet, differences in ancestry are not proof of inherent differences, genetic or otherwise, between individuals.

What’s next?
The next-generation of DNA microarray-based technologies will allow equal detection of large and small
CNVs. Also on the horizon are new DNA sequencing technologies enabling rapid (and ultimately
inexpensive) ‘personalized’ genome sequencing projects. Coupled together, these technologies will capture
almost all the variation in a genome.

Databases:

Database of Genomic Variants: http://projects.tcag.ca/variation/

DECIPHER (Database of Chromosome Imbalances in Phenotypes Using Ensembl Resources):
http://www.sanger.ac.uk/PostGenomics/decipher/

Further reading
Check E. Human genome: patchwork people.
Nature. 2005 Oct 20;437(7062):1084-6.

Bob Holmes. Magic Numbers. New Scientist, 2006, April 8, 38-41.

Daar AS, Scherer SW, Hegele RA. Implications for copy-number variation in the human genome: a time for
questions. Nature Reviews Genetics, 2006, 7:414.

Feuk L, Carson AR, Scherer SW. Structural variation in the human genome.
Nature Reviews Genetics, 2006, 7:85-97.