CNV = Copy Number
Variants = Copy Number Variation
copy number (also "copy number variants" or CNVs) is the number of
copies of a particular gene in the genotype of an individual. Recent
evidence shows that the gene copy number can be elevated in cancer
The human genome is
comprised of 6 billion chemical bases (or nucleotides) of DNA packaged
into two sets
of 23 chromosomes, one set inherited from each parent. The DNA encodes
roughly 27,000 genes. It was generally thought
that genes were almost always present in two copies in a genome.
However, recent discoveries have
revealed that large segments of DNA, ranging in size from thousands to
millions of DNA bases, can vary in
copy-number. Such copy number variations (or CNVs) can encompass genes
dosage imbalances. For example, genes that were thought to always occur
in two copies per genome have now been found
to sometimes be present in one, three, or more than three copies. In a
few rare instances
the genes are missing altogether (see figure).
are CNVs important?
Differences in the
DNA sequence of our genomes contribute to our uniqueness. These changes
traits including susceptibility to disease. It was thought that single
nucleotide changes (called SNPs) in DNA were the most
prevalent and important form of genetic variation. The current studies
reveal that CNVs comprise at
least three times the total nucleotide content of SNPs. Since CNVs
often encompass genes, they may have
important roles both in human disease and drug response. Understanding
of CNV formation may also help us better understand human genome
does the new CNV map help?
The new global CNV
map will transform medical research in four areas. The first and most
important area is in hunting for genes underlying common diseases. To
date, attempts to identify these genes have not really considered the
role CNVs may play in human health. Second, the CNV map is being used
to study familial genetic conditions. Third, there are thousands
developmental defects caused by chromosomal rearrangements. The CNV map
is being used to exclude variation found in unaffected individuals,
helping researchers to target the region that might be involved. The
data generated will also contribute to a more accurate and complete
human genome reference sequence used by all biomedical scientists.
FAQ about CNV
Copy Number Variation (CNV) Project
caused by a variety of different possible alterations (mutations) in
DNA sequences. We are investigating gains and losses of large chunks of
DNA sequence consisting of between ten thousand and five million
letters (known as Copy Number Variation). This type of mutation has
often been overlooked in previous surveys of mutations that cause
genetic diseases. We do not know what proportion of genetic disease is
caused by copy number variation (CNV), but we suspect that it is
appreciable. We already know that many genetic diseases that occur in
families result from these kinds of mutation, we also know that there
are Copy Number Variants that protect against HIV infection and
malaria. The contribution of CNV to the common, complex diseases (e.g.
diabetes, heart disease) is presently unknown.
- How much copy number variation (CNV) exists
between human genomes?
- How best can CNVs be incorporated into whole
genome association studies?
- What is the contribution of copy number
variation to genetic disease?
- What is the relative contribution of different
mutational mechanisms to CNV?
- What is the genomic impact of CNV on gene
- What role has copy number variation played in
recent human evolution?
DatabasE of Chromosomal Imbalance and Phenotype
in Humans using Ensembl
of submicroscopic chromosomal
imbalance collects clinical information about chromosomal
microdeletions/duplications/insertions, translocations and inversions
and displays this information on the human genome map with the aims of:
- Increasing medical and scientific knowledge
about chromosomal microdeletions/duplications
- Improving medical care and genetic advice for
individuals/families with submicroscopic chromosomal imbalance
- Facilitating research into the study of genes
which affect human development and health
Finding copy-number variants.
Nature Methods 2008 5(11) 917
number variants (CNVs): Distribution in normal subjects and
FISH/real-time qPCR analysis.
Qiao, Xudong Liu, Chansonette Harvard, Sarah L Nolin, W Ted Brown,
Maryam Koochek, Jeanette JA Holden, ME Suzanne Lewis, and Evica
Genomics 2007, 8: 167-177
Global variation in
copy number in the human genome.
Redon, Shumpei Ishikawa, Karen R. Fitch, Lars Feuk, George H. Perry, T.
Daniel Andrews, Heike Fiegler,
Michael H. Shapero, Andrew R. Carson, Wenwei Chen4, Eun Kyung Cho,
Stephanie Dallaire, Jennifer L. Freeman,
Juan R. Gonzalez, Monica Gratacos, Jing Huang, Dimitrios
Kalaitzopoulos, Daisuke Komura,
Jeffrey R. MacDonald, Christian R. Marshall, Rui Mei, Lyndal
Montgomery, Kunihiro Nishimura,
Kohji Okamura, Fan Shen, Martin J. Somerville, Joelle Tchinda, Armand
Valsesia, Cara Woodwark,
Fengtang Yang, Junjun Zhang, Tatiana Zerjal, Jane Zhang, Lluis
Armengol, Donald F. Conrad,
Xavier Estivill, Chris Tyler-Smith, Nigel P. Carter, Hiroyuki
Aburatani, Charles Lee, Keith W. Jones,
Stephen W. Scherer & Matthew E. Hurles
(2006) Vol 444. 444-454
and objective copy number profiling using real-time
Barbara D’haene, Jo Vandesompele, Jan
Methods Vol 50, Issue 4, Pages
qPCR to a higher level: Analysis of CNV reveals the power of
high throughput qPCR to enhance quantitative resolution
Suzanne Weaver, Simant Dube, Alain Mir, Jian
Gang Sun, Ramesh Ramakrishnan, Robert C. Jones, Kenneth J. Livak
Methods Vol 50, Issue 4, Pages 271-276
Copy number variation
and evolution in humans and chimpanzees.
Perry GH, Yang F, Marques-Bonet T, Murphy C, Fitzgerald T, Lee AS,
Hyland C, Stone AC, Hurles ME, Tyler-Smith C, Eichler EE, Carter NP,
Lee C, Redon R.
Genome Res. 2008 18(11): 1698-1710
Methods to detect and analyze copynumber
variations at the genome-wideand locus-specific levels.
J.H. Lee and J.T. Jeon
Cytogenet Genome Res 123:333–342 (2008)
Methods and strategies for analyzing copy
number variation using DNA microarrays.
Nat Genet. 2007 39(7 Suppl): S16-21. Review.
Simultaneous mutation and copy number
variation (CNV) detection by multiplex PCR-based GS-FLX sequencing.
Goossens D, Moens LN, Nelis E, Lenaerts AS, Glassee W, Kalbe A, Frey B,
Kopal G, De Jonghe P, De Rijk P, Del-Favero J.
Hum Mutat. 2009 30(3): 472-476
Genome-wide analysis of transcript isoform
variation in humans.
Kwan T, Benovoy D, Dias C, Gurd S, Provencher C, Beaulieu P, Hudson TJ,
Sladek R, Majewski J.
Nat Genet. 2008 40(2): 225-231.
Transcript copy number estimation using a
mouse whole-genome oligonucleotide microarray.
Mark G Carter, Alexei A Sharov, Vincent VanBuren, Dawood B Dudekula,
Condie E Carmack, Charlie Nelson and Minoru S H Ko
Genome Biology 2005, 6:R61
Genome-wide copy-number-variation study
identified a susceptibility gene, UGT2B17, for osteoporosis.
Yang TL, Chen XD, Guo Y, Lei SF, Wang JT, Zhou Q, Pan F, Chen Y, Zhang
ZX, Dong SS, Xu XH, Yan H, Liu X, Qiu C, Zhu XZ, Chen T, Li M, Zhang H,
Zhang L, Drees BM, Hamilton JJ, Papasian CJ, Recker RR, Song XP, Cheng
J, Deng HW.
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Comparative study of three PCR-based copy
number variant approaches, CFMSA, M-PCR, and MLPA, in 22q11.2 deletion
Yang C, Zhu X, Yi L, Shi Z, Wang H, Hu Y, Wang Y.
Genet Test Mol Biomarkers. 2009 13(6): 803-808
Copy-number variation genotyping of GSTT1
and GSTM1 gene deletions by real-time PCR.
Rose-Zerilli MJ, Barton SJ, Henderson AJ, Shaheen SO, Holloway JW.
Clin Chem. 2009 55(9): 1680-1685
High-throughput genotyping of copy number
variation in glutathione S-transferases M1 and T1 using real-time PCR
in 20,687 individuals.
Nørskov MS, Frikke-Schmidt R, Loft S, Tybjaerg-Hansen A.
Clin Biochem. 2009 42(3): 201-209
Candidate gene copy number analysis by PCR
and multicapillary electrophoresis.
Szantai E, Elek Z, Guttman A, Sasvari-Szekely M.
Electrophoresis. 2009 30(7): 1098-1101.
Statistical tools for transgene copy number
estimation based on real-time PCR.
Joshua S Yuan, Jason Burris, Nathan R Stewart, Ayalew Mentewab and C
BMC Bioinformatics 2007, 8(): S6
Copy number variation goes clinical.
A meeting report
Le Caignec C, Redon R.
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changing the landscape of chromosomes and design of disease studies.
Feuk, Christian R. Marshall, Richard F. Wintle and Stephen W. Scherer
Molecular Genetics (2006) Vol. 15, Review Issue 1 R57–R66
variation: New insights in genome diversity.
L. Freeman, George H. Perry, Lars Feuk, Richard Redon, Steven
David M. Altshuler, Hiroyuki Aburatani, Keith W. Jones, Chris
Matthew E. Hurles, Nigel P. Carter, Stephen W. Scherer, and Charles Lee
Research (2006) 16:949–961
Quantitative PCR as an
Alternative to Southern Blot or Fluorescence In Situ Hybridization for
Detection of Gene Copy Number Changes.
Jasmien Hoebeeck, Frank Speleman, and Jo Vandesompele
Methods in Molecular Biology, vol. 353: 205-226
Protocols for Nucleic Acid Analysis by Nonradioactive Probes, Second
Edition Edited by: E. Hilario and J. Mackay
of the SMN gene copy number by real-time TaqMan PCR.
Gómez-Curet & Karyn G. Robinson & Vicky L. Funanage
& Thomas O. Crawford & Mena Scavina & Wenlan Wang
An accurate method for
quantifying and analyzing copy number variation in porcine KIT by an
oligonucleotide ligation assay.
Bo-Young Seo, Eung-Woo Park, Sung-Jin Ahn, Sang-Ho, Jae-Hwan Kim,
Hyun-Tae Im, Jun-Heon Lee, In-Cheol Cho, Il-Keun Kong and Jin-Tae Jeon
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Sebat, B. Lakshmi, Jennifer Troge, Joan Alexander, Janet Young, Par
Lundin, Susanne Maner, Hillary Massa, Megan Walker,
Chi, Nicholas Navin, Robert Lucito, John Healy, James Hicks, Kenny Ye,
Andrew Reiner, T. Conrad Gilliam,
Barbara Trask, Nick Patterson, Anders Zetterberg, Michael Wigler
(2004) VOL 305 525-528
Major changes in our
DNA lead to major changes in our thinking.
GENETICS SUPPLEMENT (2007) VOLUME 39 S3-S5
Accurate and reliable
high-throughput detection of copy number variation in the human genome.
Fiegler, Richard Redon, Dan Andrews, Carol Scott, Robert Andrews, Carol
Carder, Richard Clark, Oliver Dovey, Peter Ellis, Lars Feuk, Lisa
Hunt,1 Dimitrios Kalaitzopoulos, James Larkin, Lyndal Montgomery, George
H. Perry, Bob
W. Plumb, Keith Porter, Rachel E. Rigby, Diane Rigler, Armand
Cordelia Langford, Sean J. Humphray, Stephen W. Scherer, Charles
E. Hurles, and Nigel P. Carter
Research (2006) 16:1566–1574
Relevance of BAC
transgene copy number in mice: transgene copy number variation across
multiple transgenic lines and correlations with
integrity and expression.
J. Chandler Ronald L. Chandler Eva M. Broeckelmann Yue Hou E. Michelle
Southard-Smith Douglas P. Mortlock
Genome (2007) 18: 693–708
large-scale variation in the human genome.
John Iafrate, Lars Feuk, Miguel N Rivera, Marc L Listewnik, Patricia K
Donahoe, Ying Qi, Stephen W Scherer & Charles Lee
GENETICS (2004) VOLUME 36 NUMBER 9 949-951
Real-Time Invader Assay (mPCR-RETINA): A Novel SNP-Based Method for
Detecting Allelic Asymmetries Within Copy Number Variation Regions.
Hosono, Michiaki Kubo, Yumiko Tsuchiya, Hiroko Sato, Takuya Kitamoto,
Susumu Saito, Yozo Ohnishi, and Yusuke Nakamura
MUTATION (2007) 0,1-8
between mitochondrial DNA copy number and lipogenesis in human white
Kaaman & L. M. Sparks & V. van Harmelen & S. R. Smith &
E. Sjölin & I. Dahlman & P. Arner
(2007) 50: 2526–2533
comparison identifies structural variants in the human genome.
Khaja, Junjun Zhang, Jeffrey R MacDonald, Yongshu He, Ann M
Joseph-George, John Wei, Muhammad A Rafiq,
Cheng Qian, Mary Shago, Lorena Pantano, Hiroyuki Aburatani, Keith
Redon, Matthew Hurles, Lluis Armengol, Xavier Estivill, Richard J
Mural, Charles Lee, Stephen W Scherer
& Lars Feuk
GENETICS (2006) VOLUME 38 NUMBER 12 1413-1418
alpha mRNA copy numbers in immunohistochemically ERα-positive-,
and negative breast cancer tissues.
Poola and Qingqi Yue
Cancer 2007, 7: 56-66
measurement of DNA copy number changes in neuroblastoma: dissecting
amplicons and mapping losses, gains and breakpoints.
Michels, J. Vandesompele, J. Hoebeeck, B. Menten, K. De Preter, G.
Laureys, N. Van Roy, F. Speleman
Genome Res (2006) 115: 273–282
Synthesis in Mammalian Cells.
Raj, Charles S. Peskin, Daniel Tranchina, Diana Y. Vargas, Sanjay Tyagi
(2006) Volume 4 Issue 10 e309
Specific Real-Time Polymerase Chain Reaction Assays to Accurately
Determine Copy Number Variations (CNVs) of Human Complement C4A, C4B,
C4-Long, C4-Short, and RCCX Modules:
Elucidation of C4 CNVs in 50 Consanguineous
Subjects with Defined HLA Genotypes1.
Ling Wu, Stephanie L. Savelli, Yan Yang, Bi Zhou, Brad H. Rovin, Daniel
J. Birmingham, Haikady N. Nagaraja, Lee A. Hebert, and C. Yung Yu
Journal of Immunology (2007) 179: 3012–3025
bioinformatics resources for
display and analysis of copy number and other structural variants in
the human genome.
J. Zhang, L. Feuk, G.E. Duggan, R. Khaja, S.W. Scherer
Cytogenet Genome Res (2006) 115:205–214
relative QPCR quantification of plasmid copy number in Escherichia coli.
Changsoo Lee, Jaai Kim, Seung Gu Shin, Seokhwan Hwang
Journal of Biotechnology (2006) 123: 273–280