Jump to content

Copy number variation

From Wikipedia, the free encyclopedia

This is an old revision of this page, as edited by Rinikcr89 (talk | contribs) at 17:03, 14 February 2016 (Reworded the introduction). The present address (URL) is a permanent link to this revision, which may differ significantly from the current revision.

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 are different from single-nucleotide polymorphisms (SNPs), which affect only one single nucleotide base.

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.[2][3] 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from broken DNA at one replication fork invading another fork, resulting in a template switch.[4] This was subsequently superseded by a more general microhomology-mediated break-induced replication (MMBIR) model.[5]

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.[6] 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.[7]

CNV in short repeated DNA sequences called microsatellites can arise through additional mechanisms including replication slippage and defective mismatch repair.[8][9] 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.[10][11][12][13]

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.[14][15]

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.[16] [17]

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.[18][19] It is estimated that approximately 0.4% of the genome of unrelated people typically differ with respect to copy number.[20] De novo CNVs have been observed between identical twins who otherwise have identical genomes.[21]

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.[22] In addition, a higher copy number of CCL3L1 has been associated with lower susceptibility to HIV infection,[23] 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.[24] Copy number variation has also been associated with autism,[25][26][27][28] schizophrenia,[25][29] and idiopathic learning disability.[30]

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.[31]

Among common functional CNVs, gene gains outnumber losses, suggesting that many of them are favored in evolution and, therefore, beneficial in some way.[32] 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.[17]

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. PMID 20059347.
  2. ^ Piotrowski, A; Bruder, CE; Andersson, R; Diaz de Ståhl, T; Menzel, U; Sandgren, J; Poplawski, A; von Tell, D; Crasto, C; Bogdan, A; Bartoszewski, R; Bebok, Z; Krzyzanowski, M; Jankowski, Z; Partridge, EC; Komorowski, J; Dumanski, JP (September 2008). "Somatic mosaicism for copy number variation in differentiated human tissues". Human Mutation. 29 (9): 1118–24. doi:10.1002/humu.20815. PMID 18570184.
  3. ^ Abyzov, A; Mariani, J; Palejev, D; Zhang, Y; Haney, MS; Tomasini, L; Ferrandino, AF; Rosenberg Belmaker, LA; Szekely, A; Wilson, M; Kocabas, A; Calixto, NE; Grigorenko, EL; Huttner, A; Chawarska, K; Weissman, S; Urban, AE; Gerstein, M; Vaccarino, FM (20 December 2012). "Somatic copy number mosaicism in human skin revealed by induced pluripotent stem cells". Nature. 492 (7429): 438–42. Bibcode:2012Natur.492..438A. doi:10.1038/nature11629. PMID 23160490.
  4. ^ 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.
  5. ^ 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}}: CS1 maint: multiple names: authors list (link)
  6. ^ 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.
  7. ^ Cheng, Z.; Ventura, M.; She, X.; Khaitovich, P.; Graves, T.; Osoegawa, K.; Church, D.; Dejong, P.; Wilson, K.; Pääbo, S.; Rocchi, M.; Eichler, E. E. (September 2005). "A genome-wide comparison of recent chimpanzee and human segmental duplications". Nature. 437 (7055): 88–93. Bibcode:2005Natur.437...88C. doi:10.1038/nature04000. ISSN 0028-0836. PMID 16136132.
  8. ^ Li, YC; Korol, AB; Fahima, T; Nevo, E (June 2004). "Microsatellites within genes: structure, function, and evolution". Molecular Biology and Evolution. 21 (6): 991–1007. doi:10.1093/molbev/msh073. PMID 14963101.
  9. ^ Slean, MM; Panigrahi, GB; Ranum, LP; Pearson, CE (1 July 2008). "Mutagenic roles of DNA "repair" proteins in antibody diversity and disease-associated trinucleotide repeat instability". DNA repair. 7 (7): 1135–54. doi:10.1016/j.dnarep.2008.03.014. PMID 18485833.
  10. ^ 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.
  11. ^ 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.
  12. ^ 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.
  13. ^ Paudel Y; et al. (2013). "Evolutionary dynamics of copy number variation in pig genomes in the context of adaptation and domestication". BMC Genomics. 14 (1): 449. doi:10.1186/1471-2164-14-449. PMC 3716681. PMID 23829399.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  14. ^ 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.
  15. ^ 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.
  16. ^ 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)
  17. ^ 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.
  18. ^ 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.
  19. ^ 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.
  20. ^ Kidd JM, Cooper GM, Donahue WF; et al. (May 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}}: CS1 maint: multiple names: authors list (link)
  21. ^ "Human Genetic Variation Fact Sheet". National Institute of General Medical Sciences (NIH). July 2008. Retrieved 16 August 2008.
  22. ^ 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.
  23. ^ 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.
  24. ^ 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.
  25. ^ 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.
  26. ^ 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.
  27. ^ 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.
  28. ^ Gai X; et al. (2011). "Rare structural variation of synapse and neurotransmission genes in autism". Mol Psychiatry. 17 (4): 402–11. doi:10.1038/mp.2011.10. PMC 3314176. PMID 21358714.
  29. ^ St Clair D (2008). "Copy number variation and schizophrenia". Schizophr Bull. 35 (1): 9–12. doi:10.1093/schbul/sbn147. PMC 2643970. PMID 18990708.
  30. ^ 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.
  31. ^ Craddock N, Hurles ME, Cardin N; et al. (April 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}}: CS1 maint: multiple names: authors list (link)
  32. ^ 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

Retrieved from "https://en.wikipedia.org/w/index.php?title=Copy_number_variation&oldid=704951230"