copy number variants

Submicroscopic (less than 2 Mb) segmental DNA copy number changes are a recently recognized source of genetic variability between individuals. The biological consequences of copy number variants (CNVs) are largely undefined.

In some cases, CNVs that cause gene dosage effects have been implicated in phenotypic variation. CNVs have been detected in diverse species, including mice and humans.

Deletions and duplications of chromosomal segments (copy number variants, CNVs) are a major source of variation between individual humans and are an underlying factor in human evolution and in many diseases, including mental illness, developmental disorders and cancer.

CNVs form at a faster rate than other types of mutation, and seem to do so by similar mechanisms in bacteria, yeast and humans.

Non-homologous end-joining mechanisms are well known, but recent models focus on perturbation of DNA replication and replication of non-contiguous DNA segments.

For example, cellular stress might induce repair of broken replication forks to switch from high-fidelity homologous recombination to non-homologous repair, thus promoting copy number change.

Pathology

Inter-individual copy number variation is a considerable and unanticipated plasticity of the human genome. These structural changes constitute a major source of inter-individual genetic variation that could explain variable penetrance of inherited (Mendelian and polygenic) diseases and variation in the phenotypic expression of aneuploidies and sporadic traits, and might represent a major factor in the aetiology of complex, multifactorial traits.

Copy number variations (CNVs) within the human genome contribute to nucleotide diversity to a larger extent than single nucleotide polymorphisms (SNPs).

The contribution of CNVs to human disease susceptibility may be greater than previously expected, although a complete understanding of the phenotypic consequences of CNVs is incomplete.

Segmental copy-number variations (CNVs) in the human genome are associated with developmental disorders and susceptibility to diseases. More importantly, CNVs may represent a major genetic component of our phenotypic diversity.

Copy-number variations (CNVs) of somatic cells

The exploration of copy-number variation (CNV), notably of somatic cells, is an understudied aspect of genome biology. Any differences in the genetic makeup between twins derived from the same zygote represent an irrefutable example of somatic mosaicism. CNVs exist within pairs of monozygotic twins with either concordant or discordant phenotype. (18304490)

Types

 autosomal segmental CNVs

See also

 Oncobase
 SNPs
 CNVs associatito identify
 complex traits.

References

 Mechanisms of change in gene copy number. Hastings PJ, Lupski JR, Rosenberg SM, Ira G. Nat Rev Genet. 2009 Aug;10(8):551-64. PMID: 19597530

 Bruder CE, Piotrowski A, Gijsbers AA, Andersson R, Erickson S, de Ståhl TD, Menzel U, Sandgren J, von Tell D, Poplawski A, Crowley M, Crasto C, Partridge EC, Tiwari H, Allison DB, Komorowski J, van Ommen GJ, Boomsma DI, Pedersen NL, den Dunnen JT, Wirdefeldt K, Dumanski JP. Phenotypically concordant and discordant monozygotic twins display different DNA copy-number-variation profiles. Am J Hum Genet. 2008 Mar;82(3):763-71. PMID: 18304490

 Perry GH, Ben-Dor A, Tsalenko A, Sampas N, Rodriguez-Revenga L, Tran CW, Scheffer A, Steinfeld I, Tsang P, Yamada NA, Park HS, Kim JI, Seo JS, Yakhini Z, Laderman S, Bruhn L, Lee C. The fine-scale and complex architecture of human copy-number variation.Am J Hum Genet. 2008 Mar;82(3):685-95. PMID: 18304495

 Marshall CR, Noor A, Vincent JB, Lionel AC, Feuk L, Skaug J, Shago M, Moessner R, Pinto D, Ren Y, Thiruvahindrapduram B, Fiebig A, Schreiber S, Friedman J, Ketelaars CE, Vos YJ, Ficicioglu C, Kirkpatrick S, Nicolson R, Sloman L, Summers A, Gibbons CA, Teebi A, Chitayat D, Weksberg R, Thompson A, Vardy C, Crosbie V, Luscombe S, Baatjes R, Zwaigenbaum L, Roberts W, Fernandez B, Szatmari P, Scherer SW. Structural variation of chromosomes in autism spectrum disorder. Am J Hum Genet. 2008 Feb;82(2):477-88. PMID: 18252227

 Kosta K, Sabroe I, Goke J, Nibbs RJ, Tsanakas J, Whyte MK, Teare MD. A bayesian approach to copy-number-polymorphism analysis in nuclear pedigrees. Am J Hum Genet. 2007 Oct;81(4):808-12. PMID: 17847005

 Beckmann JS, Estivill X, Antonarakis SE. Copy number variants and genetic traits: closer to the resolution of phenotypic to genotypic variability. Nat Rev Genet. 2007 Aug;8(8):639-46. PMID: 17637735

 Wong KK, deLeeuw RJ, Dosanjh NS, Kimm LR, Cheng Z, Horsman DE, MacAulay C, Ng RT, Brown CJ, Eichler EE, Lam WL. A comprehensive analysis of common copy-number variations in the human genome. Am J Hum Genet. 2007 Jan;80(1):91-104. Epub 2006 Dec 5. PMID: 17160897

 Komura D, Shen F, Ishikawa S, Fitch KR, Chen W, Zhang J, Liu G, Ihara S, Nakamura H, Hurles ME, Lee C, Scherer SW, Jones KW, Shapero MH, Huang J, Aburatani H. Genome-wide detection of human copy number variations using high-density DNA oligonucleotide arrays. Genome Res. 2006 Dec;16(12):1575-84. PMID: 17122084

 Carter NP. As normal as normal can be? Nat Genet. 2004 Sep;36(9):931-2. PMID: 15340426

 Bar-Shira A, Rosner G, Rosner S, Goldstein M, Orr-Urtreger A. Array-based comparative genome hybridization in clinical genetics. Pediatr Res. 2006 Sep;60(3):353-8. PMID: 16857771

 Schoumans J, Ruivenkamp C, Holmberg E, Kyllerman M, Anderlid BM, Nordenskjold M. Detection of chromosomal imbalances in children with idiopathic mental retardation by array based comparative genomic hybridisation (array-CGH). J Med Genet. 2005 Sep;42(9):699-705. PMID: 16141005