The distribution of copy number variation in the human genome among 270 HapMap samples [Click on image for enlagement]
Genetic diseases are 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.
Genome-wide CGH comparing two HapMap donors with approximately 27,000 BACs. [Click on image for enlagement]
Mutations (of any type) that increase the chance of an individual developing a common disease are also likely to be found at reasonable frequencies in apparently healthy populations. A range of promising new technologies should, for the first time, allow us to scan the entire human genome for CNV in a single experiment. We are comparing these new technologies for screening hundreds of apparently healthy individuals for CNV.
Using these technologies we are characterising functionally-relevant CNVs at as high resolution as possible, incorporating these variants within association studies for complex diseases, and developing a public resource to facilitate integration of CNV within medical genetic studies.
The copy number variation project draws upon expertise present in several different groups at the Sanger Institute, including: new sequencing technologies, microarray-based analyses, cytogenetics, population genetics, comparative genomics and bioinformatics.
In addition, we have established an international consortium to enable us to achieve our objectives. Together with Charles Lee (Harvard Medical School) and Steve Scherer (Hospital for Sick Kids, Toronto) we are working closely with the developers of leading edge commercial platforms to optimise technologies capable of revealing copy number variation at the highest resolution.
An ~11kb deletion on chromosome 8 revealed by ultra-high resolution CGH. Blue lines: individuals with two copies. Red line: individual with zero copies. [Click on image for enlagement]
References:
| A robust statistical method for case-control association testing with copy number variation. Barnes C, Plagnol V, Fitzgerald T, Redon R, Marchini J, Clayton D, Hurles ME Nat Genet. 2008;40;1245-52. PMID: 18776912 DOI: 10.1038/ng.206 |
| 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;. PMID: 18775914 DOI: 10.1101/gr.082016.108 |
| Adaptive evolution of UGT2B17 copy-number variation. Xue Y, Sun D, Daly A, Yang F, Zhou X, Zhao M, Huang N, Zerjal T, Lee C, Carter NP, Hurles ME, Tyler-Smith C Am J Hum Genet. 2008;83;337-46. PMID: 18760392 DOI: 10.1016/j.ajhg.2008.08.004 |
| Breaking the waves: improved detection of copy number variation from microarray-based comparative genomic hybridization. Marioni JC, Thorne NP, Valsesia A, Fitzgerald T, Redon R, Fiegler H, Andrews TD, Stranger BE, Lynch AG, Dermitzakis ET, Carter NP, Tavaré S, Hurles ME Genome Biol. 2007;8;R228. PMID: 17961237 DOI: 10.1186/gb-2007-8-10-r228 |
| Diet and the evolution of human amylase gene copy number variation. Perry GH, Dominy NJ, Claw KG, Lee AS, Fiegler H, Redon R, Werner J, Villanea FA, Mountain JL, Misra R, Carter NP, Lee C, Stone AC Nat Genet. 2007;39;1256-60. PMID: 17828263 DOI: 10.1038/ng2123 |
| Relative impact of nucleotide and copy number variation on gene expression phenotypes. Stranger BE, Forrest MS, Dunning M, Ingle CE, Beazley C, Thorne N, Redon R, Bird CP, de Grassi A, Lee C, Tyler-Smith C, Carter N, Scherer SW, Tavaré S, Deloukas P, Hurles ME, Dermitzakis ET Science. 2007;315;848-53. PMID: 17289997 DOI: 10.1126/science.1136678 |
| Global variation in copy number in the human genome. Redon R, Ishikawa S, Fitch KR, Feuk L, Perry GH, Andrews TD, Fiegler H, Shapero MH, Carson AR, Chen W, Cho EK, Dallaire S, Freeman JL, González JR, Gratacòs M, Huang J, Kalaitzopoulos D, Komura D, Macdonald JR, Marshall CR, Mei R, Montgomery L, Nishimura K, Okamura K, Shen F, Somerville MJ, Tchinda J, Valsesia A, Woodwark C, Yang F, Zhang J, Zerjal T, Zhang J, Armengol L, Conrad DF, Estivill X, Tyler-Smith C, Carter NP, Aburatani H, Lee C, Jones KW, Scherer SW, Hurles ME Nature. 2006;444;444-454. PMID: 17122850 DOI: 10.1038/nature05329 |
| Accurate and reliable high-throughput detection of copy number variation in the human genome. Fiegler H, Redon R, Andrews D, Scott C, Andrews R, Carder C, Clark R, Dovey O, Ellis P, Feuk L, French L, Hunt P, Kalaitzopoulos D, Larkin J, Montgomery L, Perry GH, Plumb BW, Porter K, Rigby RE, Rigler D, Valsesia A, Langford C, Humphray SJ, Scherer SW, Lee C, Hurles ME, Carter NP Genome Res. 2006;16;1566-74. PMID: 17122085 DOI: 10.1101/gr.5630906 |
| Genome-wide detection of human copy number variations using high-density DNA oligonucleotide arrays. 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 Res. 2006;16;1575-84. PMID: 17122084 DOI: 10.1101/gr.5629106 |
| Genome assembly comparison identifies structural variants in the human genome. Khaja R, Zhang J, Macdonald JR, He Y, Joseph-George AM, Wei J, Rafiq MA, Qian C, Shago M, Pantano L, Aburatani H, Jones K, Redon R, Hurles M, Armengol L, Estivill X, Mural RJ, Lee C, Scherer SW, Feuk L Nat Genet. 2006;38;1413-8. PMID: 17115057 DOI: 10.1038/ng1921 |
| A high-resolution survey of deletion polymorphism in the human genome. Conrad DF, Andrews TD, Carter NP, Hurles ME, Pritchard JK Nat Genet. 2006;38;75-81. PMID: 16327808 |
| How homologous recombination generates a mutable genome. Hurles M Hum Genomics. 2005;2;179-86. PMID: 16197735 |
| Origins of chromosomal rearrangement hotspots in the human genome: evidence from the AZFa deletion hotspots. Hurles ME, Willey D, Matthews L, Hussain SS Genome Biol. 2004;5;R55. PMID: 15287977 |
| Detection of large-scale variation in the human genome. Iafrate AJ, Feuk L, Rivera MN, Listewnik ML, Donahoe PK, Qi Y, Scherer SW, Lee C Nat Genet. 2004;36;949-51. PMID: 15286789 DOI: 10.1038/ng1416 |
| Microarray based comparative genomic hybridisation (array-CGH) detects submicroscopic chromosomal deletions and duplications in patients with learning disability/mental retardation and dysmorphic features. Shaw-Smith C, Redon R, Rickman L, Rio M, Willatt L, Fiegler H, Firth H, Sanlaville D, Winter R, Colleaux L, Bobrow M, Carter NP J Med Genet. 2004;41;241-8. PMID: 15060094 |
