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Copy number variation

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This gene duplication has created a copy-number variation. The chromosome now has two copies of this section of DNA, rather than one.

Copy-number variations (CNVs) are a form of structural variation that manifest as deletions or duplications in the genome. 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"). Cells with CNVs have abnormal or, for certain genes, normal variations in their copy number.

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.[1] CNVs affect segments of DNA and are thus, different from single-nucleotide polymorphisms (SNPs), which affect only one single nucleotide base.

CNV has been studied between individuals, but there is also evidence of substantial CNV between tissues within each individual, and even among different cells of the same tissue. The link between somatic CNV and cancer is well established. The functional effects of somatic CNV in patients with no history of cancer is not yet well understood. Somatic CNV appears more likely to occur in dividing tissues like liver, pancreas, and small intestine compared with non-dividing tissues like brain suggesting that CNVs may commonly arise during normal cell growth and division due to imperfect DNA replication. Somatic CNVs were observed to be modestly enriched in genes involved in regulatory processes in the cell like regulation of phosphorylation, regulation of primary metabolic processes, and regulation of gene expression.[2] It is not yet known whether somatic DNA plasticity confers a selective advantage, but it stands to reason that like germ line genetic mutation, it confers an advantage in some cases and a disadvantage in others. A step-wise theory of cancer posits that cancer arises from a single cell of origin that acquires genetic variability. Of the clonal population of cells that descend from it, some acquire additional mutations conferring selective advantage. This process continues sequentially until aggressive subpopulations of cells with many genetic alterations are recognized as malignancies that can invade and metastasize. [3][4][5]


Origins of CNVs

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.[6][7][8] 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.[9] This was subsequently superseded by a more general microhomology-mediated break-induced replication (MMBIR) model.[10]

Some genomic regions are more susceptible to CNVs. For example, Low copy repeats (LCRs), which are region-specific repeat sequences, are susceptible to 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.[11] 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.[12]

CNV in short repeated DNA sequences called microsatellites can arise through additional mechanisms including replication slippage and defective mismatch repair.[13][14] The resulting microsatellite instability is characteristic of some cancers and underlies a family of genetic disorders including Huntington's disease and myotonic dystrophy.

Detection

CNVs can be detected by a process of copy number analysis using 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.[15][16][17][18]

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.[19][20]

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.[21] [22]

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.[23][24] It is estimated that approximately 0.4% of the genome of unrelated people typically differ with respect to copy number.[25] De novo CNVs have been observed between identical twins who otherwise have identical genomes.[26]

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.[27] In addition, a higher copy number of CCL3L1 has been associated with lower susceptibility to HIV infection,[28] 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.[29] Copy number variation has also been associated with autism,[30][31][32][33] schizophrenia,[30][34] and idiopathic learning disability.[35]

However, although once touted as the explanation for the elusive hereditary causes of complex diseases like rheumatoid arthritis, the most common CNVs have little or no role in causing disease.[36]

Among common functional CNVs, gene gains outnumber losses, suggesting that many of them are favored in evolution and, therefore, beneficial in some way.[37] 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.[22]

See also

References

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Further reading

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