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)—a form of structural variation—are alterations of the DNA of a genome that results in the cell having an abnormal 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 12% of human genomic DNA and each variation may range from about one kilobase (1,000 nucleotide bases) to several megabases in size.[1] CNVs contrast with single-nucleotide polymorphisms (SNPs), which affect only one single nucleotide base.

Sources

CNVs may either be inherited or caused by de novo mutation. A recently proposed mechanism for the cause of some CNVs was fork stalling and template switching, a replication misstep.[2] However, this model was subsequently superseded by microhomology-mediated break-induced replication (MMBIR).[3]

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.[4] 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.[5]

Identification

Copy number variation can be discovered by cytogenetic techniques such as fluorescent in situ hybridization, comparative genomic hybridization, array comparative genomic hybridization, and by virtual karyotyping with SNP arrays. Recent advances in DNA sequencing technology have further enabled the identification of CNVs by next-generation sequencing.[6][7][8]

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.[9][10]

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.[11] [12]

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.[13][14] It is estimated that approximately 0.4% of the genomes of unrelated people typically differ with respect to copy number.[15] De novo CNVs have been observed between identical twins who otherwise have identical genomes.[16]

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.[17] In addition, a higher copy number of CCL3L1 has been associated with lower susceptibility to HIV infection,[18] 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.[19] Copy number variation has also been associated with autism,[20][21][22][23] schizophrenia,[20][24] and idiopathic learning disability.[25]

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.[26]

Among common functional CNVs, gene gains outnumber losses, suggesting that many of them are favored in evolution and, therefore, beneficial in some way.[27] One example of CNV is the human salivary amylase gene (AMY1). 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.[12]

See also

References

  1. ^ Pawel Stankiewicz, James R. Lupski (2010). "Structural Variation in the Human Genome and its Role in Disease". Annual Review of Medicine. 61: 437–455. doi:10.1146/annurev-med-100708-204735.
  2. ^ Lee JA, Carvalho CM, Lupski JR (2007). "A DNA replication mechanism for generating nonrecurrent rearrangements associated with genomic disorders". Cell. 131 (7): 1235–47. doi:10.1016/j.cell.2007.11.037. PMID 18160035.{{cite journal}}: CS1 maint: multiple names: authors list (link) reported in "Copy Number Variation May Stem From Replication Misstep". ScienceDaily. 4 January 2008.
  3. ^ Hastings PJ, Lupski JR, Rosenberg SM, Ira G (2009). "Mechanisms of change in gene copy number". Nature Reviews Genetics. 10 (8): 551–564. doi:10.1038/nrg2593. PMC 2864001. PMID 19597530. {{cite journal}}: Unknown parameter |unused_data= ignored (help)CS1 maint: multiple names: authors list (link)
  4. ^ Lee JA, Lupski JR (2006). "Genomic rearrangements and gene copy-number alterations as a cause of nervous system disorders". Neuron. 52 (1): 103–121. doi:10.1016/j.neuron.2006.09.027. PMID 17015230.
  5. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1038/nature04000, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1038/nature04000 instead.
  6. ^ Korbel JO; et al. (2007). "Paired-end mapping reveals extensive structural variation in the human genome". Science. 318 (5849): 420–426. Bibcode:2007Sci...318..420K. doi:10.1126/science.1149504. PMC 2674581. PMID 17901297. {{cite journal}}: Explicit use of et al. in: |author= (help)
  7. ^ Sudmant PH; et al. (2010). "Diversity of human copy number variation and multicopy genes". Science. 330 (6004): 641–646. Bibcode:2010Sci...330..641S. doi:10.1126/science.1197005. PMC 3020103. PMID 21030649. {{cite journal}}: Explicit use of et al. in: |author= (help)
  8. ^ Mills RE; et al. (2011). "Mapping copy number variation by population-scale genome sequencing". Nature. 470 (7332): 59–65. Bibcode:2011Natur.470...59.. doi:10.1038/nature09708. PMC 3077050. PMID 21293372. {{cite journal}}: Explicit use of et al. in: |author= (help)
  9. ^ Redon J; et al. (2006). "Global variation in copy number in the human genome". Nature. 444 (7118): 444–454. Bibcode:2006Natur.444..444R. doi:10.1038/nature05329. PMC 2669898. PMID 17122850. {{cite journal}}: Explicit use of et al. in: |author= (help)
  10. ^ Freeman JL; et al. (2006). "Copy number variation: New insights into genome diversity". Genome Research. 16 (8): 949–61. doi:10.1101/gr.3677206. PMID 16809666. {{cite journal}}: Explicit use of et al. in: |author= (help)
  11. ^ Atkinson M, Savageau M, Myers JT, Ninfa A (2003). "Development of Genetic Circuitry Exhibiting Toggle Switch Behavior in Escherichia Coli". Cell. 113 (5): 597–607. doi:10.1016/S0092-8674(03)00346-5. PMID 12787501.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  12. ^ a b Perry GH; et al. (2007). "Diet and evolution of human amylase gene copy number variation". Nature Genetics. 39 (10): 1256–60. doi:10.1038/ng2123. PMC 2377015. PMID 17828263. {{cite journal}}: Explicit use of et al. in: |author= (help)
  13. ^ Sebat J; et al. (2004). "Large-scale copy number polymorphism in the human genome". Science. 305 (5683): 525–528. Bibcode:2004Sci...305..525S. doi:10.1126/science.1098918. PMID 15273396. {{cite journal}}: Explicit use of et al. in: |author= (help)
  14. ^ Iafrate A; et al. (2004). "Detection of large-scale variation in the human genome". Nature Genetics. 36 (9): 949–51. doi:10.1038/ng1416. PMID 15286789. {{cite journal}}: Explicit use of et al. in: |author= (help)
  15. ^ Kidd JM, Cooper GM, Donahue WF; et al. (2008). "Mapping and sequencing of structural variation from eight human genomes". Nature. 453 (7191): 56–64. Bibcode:2008Natur.453...56K. doi:10.1038/nature06862. PMC 2424287. PMID 18451855. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  16. ^ "Human Genetic Variation Fact Sheet". National Institute of General Medical Sciences (NIH). July 2008. Retrieved 16 August 2008.
  17. ^ Cappuzzo F, Hirsch; et al. (2005). "Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer". Journal of the National Cancer Institute. 97 (9): 643–655. doi:10.1093/jnci/dji112. PMID 15870435. {{cite journal}}: Explicit use of et al. in: |author= (help)
  18. ^ Gonzalez E; et al. (2005). "The Influence of CCL3L1 Gene-Containing Segmental Duplications on HIV-1/AIDS Susceptibility". Science. 307 (5714): 1434–1440. Bibcode:2005Sci...307.1434G. doi:10.1126/science.1101160. PMID 15637236. {{cite journal}}: Explicit use of et al. in: |author= (help)
  19. ^ Aitman TJ; et al. (2006). "Copy number polymorphism in Fcgr3 predisposes to glomerulonephritis in rats and humans". Nature. 439 (7078): 851–855. Bibcode:2006Natur.439..851A. doi:10.1038/nature04489. PMID 16482158. {{cite journal}}: Explicit use of et al. in: |author= (help)
  20. ^ a b Cook EH, Scherer SW (2008). "Copy-number variations associated with neuropsychiatric conditions". Nature. 455 (7215): 919–23. Bibcode:2008Natur.455..919C. doi:10.1038/nature07458. PMID 18923514.
  21. ^ Pinto J; et al. (2010). "Functional impact of global rare copy number variation in autism spectrum disorders". Nature. 466 (7304): 368–72. Bibcode:2010Natur.466..368P. doi:10.1038/nature09146. PMC 3021798. PMID 20531469. {{cite journal}}: Explicit use of et al. in: |author= (help)
  22. ^ Sebat J; et al. (2007). "Strong association of de novo copy number mutations with autism". Science. 316 (5823): 445–9. Bibcode:2007Sci...316..445S. doi:10.1126/science.1138659. PMC 2993504. PMID 17363630. {{cite journal}}: Explicit use of et al. in: |author= (help)
  23. ^ Gai X; et al. (2011). "Rare structural variation of synapse and neurotransmission genes in autism". Mol Psychiatry. 17 (4). doi:10.1038/mp.2011.10. {{cite journal}}: Explicit use of et al. in: |author= (help)
  24. ^ St Clair D (2008). "Copy number variation and schizophrenia". Schizophr Bull. 35 (1): 9–12. doi:10.1093/schbul/sbn147. PMC 2643970. PMID 18990708.
  25. ^ Knight S; et al. (1999). "Subtle chromosomal rearrangements in children with unexplained mental retardation". The Lancet. 354 (9191): 1676–81. doi:10.1016/S0140-6736(99)03070-6. PMID 10568569. {{cite journal}}: Explicit use of et al. in: |author= (help)
  26. ^ Craddock N, Hurles ME, Cardin N; et al. (2010). "Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls". Nature. 464 (7289): 713–20. Bibcode:2010Natur.464..713T. doi:10.1038/nature08979. PMC 2892339. PMID 20360734. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  27. ^ Feng Zhang, Wenli Gu, Matthew E. Hurles, and James R. Lupski (2009). "Copy Number Variation in Human Health, Disease, and Evolution". Annu. Rev. Genomics Hum. Genet.{{cite journal}}: CS1 maint: multiple names: authors list (link)

Further reading

External links

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