Copy-number variations (CNVs)—a form of structural variation—are alterations of the DNA of a genome that results in the cell having an abnormal or, for certain genes, a normal variation in the number of copies of one or more sections of the DNA. CNVs correspond to relatively large regions of the genome that have been deleted (fewer than the normal number) or duplicated (more than the normal number) on certain chromosomes. For example, the chromosome that normally has sections in order as
A-B-C-D might instead have sections
A-B-C-C-D (a duplication of "C") or
A-B-D (a deletion of "C").
This variation accounts for roughly 13% of human genomic DNA and each variation may range from about one kilobase (1,000 nucleotide bases) to several megabases in size. CNVs contrast with single-nucleotide polymorphisms (SNPs), which affect only one single nucleotide base.
Most CNVs are stable and heritable, so CNV between individuals is largely a product of genetic heritage, however, de novo CNVs arise through diverse mechanisms at various stages of development. Multiple homologous recombination reactions on each chromosome are required for the meiotic cell divisions that give rise to gametes, and although these events are of very high fidelity, occasional mistakes are inevitable. Therefore, most CNV in the human genome likely arises through non-allelic homologous recombination events in which unmatched regions of chromosomes are mistakenly recombined during meiosis. However, two lines of evidence suggest that this is not the whole story. Firstly, various studies have revealed extensive CNV between different cells in the same individuals; these CNVs must have arisen post-fertilisation. Secondly, some complex genetic rearrangements cannot be readily reconciled with a non-allelic homologous recombination mechanism; these have been proposed to arise through rare replication defects resulting from broken DNA at one replication fork invading another fork, resulting in a template switch. This was subsequently superseded by a more general microhomology-mediated break-induced replication (MMBIR) model.
CNVs can be caused by structural rearrangements of the genome such as deletions, duplications, inversions, and translocations. Low copy repeats (LCRs), which are region-specific repeat sequences, are susceptible to such genomic rearrangements resulting in CNVs. Factors such as size, orientation, percentage similarity and the distance between the copies influence the susceptibility of LCRs to genomic rearrangement. Segmental Duplications (SDs) map near ancestral duplication sites in a phenomenon called duplication shadowing which describes the observation of a ~10 fold increased probability of duplication in regions flanking duplications versus other random regions.
CNV in short repeated DNA sequences called microsatellites can arise through additional mechanisms including replication slippage and defective mismatch repair. The resulting microsatellite instability is characteristic of some cancers and underlies a family of genetic disorders including Huntington's disease and myotonic dystrophy.
Copy number variation can be discovered by cytogenetic techniques such as fluorescent in situ hybridization, comparative genomic hybridization, array comparative genomic hybridization, end-sequence profiling and by virtual karyotyping with SNP arrays. Recent advances in DNA sequencing technology have further enabled the identification of CNVs by next-generation sequencing.
CNVs can be limited to a single gene or include a contiguous set of genes. CNVs can result in having either too many or too few of the dosage-sensitive genes, which may be responsible for a substantial amount of human phenotypic variability, complex behavioral traits and disease susceptibility.
In certain cases, such as rapidly growing Escherichia coli cells, the gene copy number can be 4-fold greater for genes located near the origin of DNA replication, rather than at the terminus of DNA replication. Elevating the gene copy number of a particular gene can increase the expression of the protein that it encodes. 
Prevalence in humans
The fact that DNA copy number variation is a widespread and common phenomenon among humans was first uncovered following the completion of the Human Genome Project. It is estimated that approximately 0.4% of the genome of unrelated people typically differ with respect to copy number. De novo CNVs have been observed between identical twins who otherwise have identical genomes.
Role in disease
Like other types of genetic variation, some CNVs have been associated with susceptibility or resistance to disease. Gene copy number can be elevated in cancer cells. For instance, the EGFR copy number can be higher than normal in non-small cell lung cancer. In addition, a higher copy number of CCL3L1 has been associated with lower susceptibility to HIV infection, and a low copy number of FCGR3B (the CD16 cell surface immunoglobulin receptor) can increase susceptibility to systemic lupus erythematosus and similar inflammatory autoimmune disorders. Copy number variation has also been associated with autism, schizophrenia, and idiopathic learning disability.
Among common functional CNVs, gene gains outnumber losses, suggesting that many of them are favored in evolution and, therefore, beneficial in some way. One example of CNV is the human salivary amylase gene (AMY1A). This gene is typically present as two diploid copies in chimpanzees. Humans average over 6 copies and may have as many as 15. This is thought to be an adaptation to a high-starch diet that improves the ability to digest starchy foods.
- Comparative genomics
- Copy number analysis
- Human genome
- Molecular evolution
- Segmental duplication
- Tandem exon duplication
- Virtual Karyotype
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- Copy Number Variation Project, Sanger Institute
- Integrative annotation platform for copy number variations in humans
- A bibliography on copy number variation
- Database of Genomic Variants, a database of structural variants in the human genome
- Copy Number Variation Detection via High-Density SNP Genotyping
- Oxford Gene Technology
- BioDiscovery Nexus Copy Number
- High-resolution mapping of copy number variations in 2,026 healthy individuals
- The 1000 Genomes Project
- cn.FARMS: a latent variable model to detect copy number variations in microarray data with a low false discovery rate, an R package —software