Copy number variation

Copy number variation is a form of structural variation in the genome and refers to differences in the number of copies of a particular region in the genome. Humans (being diploid) ordinarily have two copies of each autosomal region, one per chromosome. This may vary for particular genetic regions due to deletion or duplication.

Copy number variants (CNVs) may either be inherited or caused by "de novo" mutation. A recently proposed mechanism for the cause of some CNVs is fork stalling and template switching, a replication misstep. [cite journal | journal=Cell | volume=131 | issue=7 | pages=1235-47 | date=2007 | author=Lee JA, Carvalho CM, Lupski JR. | title=A DNA replication mechanism for generating nonrecurrent rearrangements associated with genomic disorders | pmid=18160035 | doi = 10.1016/j.cell.2007.11.037 | url=http://www.cell.com/content/article/abstract?uid=PIIS0092867407015413 reported in cite web| title= Copy Number Variation May Stem From Replication Misstep | publisher = ScienceDaily | date= 2008-01-04 | url=http://www.sciencedaily.com/releases/2007/12/071227183904.htm ]

Therefore, CNV can be caused by uniparental disomy or genomic rearrangements 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 CNV. Factors such as size, orientation, percentage similarity and the distance between the copies renders them susceptible. [Lee J.A., Lupski J.R. Genomic Rearrangements and Gene Copy-Number Alterations as a Cause of Nervous System Disorders (2006) Neuron, 52 (1), pp. 103-121.]

Copy number variation can be discovered by cytogenetic techniques such as fluorescent in situ hybridization, comparative genomic hybridization, array comparative genomic hybridization, and by large-scale SNP genotyping.The fact that DNA copy number variation is a widespread and common phenomena among humans was first uncovered [cite journal |author = Sebat J, et al.
date = 2004
title = Large-scale copy number polymorphism in the human genome
journal= Science
volume = 305
pages=525–528
pmid = 15273396
url = http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=15273396
doi = 10.1126/science.1098918] [cite journal |author=Iafrate A, et al.
date= 2004
url=http://www.nature.com/ng/journal/v36/n9/abs/ng1416.html | title= Detection of large-scale variation in the human genome
journal = Nature Genetics
volume= 36: 949-51
pmid = 15286789
doi = 10.1038/ng1416 |pages=949] following the completion of the human genome project. It is estimated that approximately 0.4% of the genomes of unrelated people typically differ with respect to copy number. "De novo" CNVs have been observed between identical twins who otherwise have identical genomes. [cite web| url = http://www.nigms.nih.gov/Publications/Factsheet_GeneticVariation.htm | title=Human Genetic Variation Fact Sheet | publisher = National Institute of General Medical Sciences (NIH) | date = July 2008 | accessdate= 2008-08-16]

Like other types of genetic variation, some gene copy number variants 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. [cite journal | author=Cappuzzo F, Hirsch, et al.
date = 2005
title = Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer
journal= Journal of the National Cancer Institute
volume= 97
pages= 643–655
pmid=15870435
doi=10.1093/jnci/dji112] In addition, a higher copy number of CCL3L1 has been associated with lower susceptibility to human HIV infection, [cite journal
author=Gonzalez, E. et al. | journal=Science| date=2005| volume=307| pages=1434–1440
title=The Influence of CCL3L1 Gene-Containing Segmental Duplications on HIV-1/AIDS Susceptibility
doi=10.1126/science.1101160 | pmid=15637236] 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. [cite journal
author= Aitman T. J. et al.| journal=Nature | date=2006
title=Copy number polymorphism in Fcgr3 predisposes to glomerulonephritis in rats and humans
doi=10.1038/nature04489 | volume=439 | pages=851–855 | pmid=16482158 ] Copy number variation has also been associated with autism, [cite journal
title= Strong association of de novo copy number mutations with autism
doi= 10.1126/science.1138659
year= 2007
author= Sebat, J., et al.
journal= Science
volume= 316
pages= 445
pmid= 17363630] schizophrenia, [cite journal
title= Large recurrent microdeletions associated with schizophrenia
doi=10.1038/nature07229
year= 2008
author= Stefansson, H., et al.
journal= Nature] and idiopathic learning disability. [cite journal
title= Subtle chromosomal rearrangements in children with unexplained mental retardation
doi= 10.1016/S0140-6736(99)03070-6
year= 1999
author= Knight, S., et al.
journal= The Lancet
volume= 354
pages= 1676] In humans, CNVs encompass more DNA than single nucleotide polymorphisms (SNPs). CNV can be limited to a single gene or include a contiguous set of genes. CNV 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. [cite journal
journal=Nature | author = Redon, J. et al | volume=444 | pages = 444–454
title=Global variation in copy number in the human genome |date = 2006
doi =10.1038/nature05329 | pmid=17122850] [cite journal | author=Freeman, JL, et al
date= 2006
title=Copy number variation: New insights into genome diversity
url=http://www.genome.org/cgi/content/abstract/16/8/949
journal = Genome Research
volume=16
pages= 949–61
pmid = 16809666
doi = 10.1101/gr.3677206]

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. [cite journal| author=Atkinson M, Savageau M, Myers JT, Ninfa A
date=2003
title=Development of Genetic Circuitry Exhibiting Toggle Switch Behavior in Escherichia Coli
journal=Cell
volume=113
pages =597
pmid=12787501
doi=10.1016/S0092-8674(03)00346-5 ] [cite journal| author=Perry, G.H. et al.
date=2007
url=http://www.nature.com/ng/journal/v39/n10/abs/ng2123.html | title=Diet and evolution of human amylase gene copy number variation
journal=Nature Genetics
volume=39
pages =1256
pmid=17828263| doi=10.1038/ng2123 ]

ources and notes

Further reading

* [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=10471496 Genome-wide analysis of DNA copy-number changes using cDNA microarrays] "Gene amplifications and deletions frequently contribute to tumorigenesis. Characterization of these DNA copy-number changes is important for both the basic understanding of cancer and its diagnosis."
*cite web|url=http://www.newscientist.com/article.ns?id=mg18324592.000 | publisher= New Scientist| date=August 7, 2004| title=Huge genetic variation in healthy people
*cite web|url=http://www.nature.com/ng/journal/v36/n9/abs/ng0904-931.html | publisher= Nature Genetics| date=September 1, 2004| title=As normal as normal can be
*cite web|url= http://www.nature.com/nature/journal/v437/n7062/full/4371084a.html | publisher= Nature| date=October 20, 2005| title=Human Genome: Patchwork people
*cite web|url= http://www.newscientist.com/article/dn10646-gene-duplications-may-define-who-you-are-.html | publisher= New Scientist| title=Human DNA is far more varied than thought | date=November 22, 2006| title=Gene duplications may define who you are
*cite web| url=http://news.nationalgeographic.com/news/2006/11/061122-human-genetics.html | publisher=National Geographic | title=DNA varies more widely from person to person, Genetic maps reveal| date=November 22, 2006
*cite web| url=http://www.nature.com/ng/journal/v39/n7s/pdf/ng0707s-S1.pdf | publisher=Nature Genetics | title=Finding the right lenses| date=July 1, 2007|format=PDF

External links

* [http://www.sickkids.ca/mediaroom/custom/CNV_FAQ.pdf What is copy number variation?]
* [http://www.sanger.ac.uk/humgen/cnv/ Copy Number Variation Project]
* [http://www.nslij-genetics.org/cnv/ A bibliography on copy number variation]
* [http://projects.tcag.ca/variation/ A database of structural variants in the human genome]