Copy number variation related disease genes

Abstract

Background: One of the most important and challenging issues in biomedicine and genomics is how to identify disease related genes. Datasets from high-throughput biotechnologies have been widely used to overcome this issue from various perspectives, e.g., epigenomics, genomics, transcriptomics, proteomics, metabolomics. At the genomic level, copy number variations (CNVs) have been recognized as critical genetic variations, which contribute significantly to genomic diversity. They have been associated with both common and complex diseases, and thus have a large influence on a variety of Mendelian and somatic genetic disorders.

Results: In this review, based on a variety of complex diseases, we give an overview about the critical role of using CNVs for identifying disease related genes, and discuss on details the different high-throughput and sequencing methods applied for CNV detection. Some limitations and challenges concerning CNV are also highlighted.

Conclusions: Reliable detection of CNVs will not only allow discriminating driver mutations for various diseases, but also helps to develop personalized medicine when integrating it with other genomic features.

Graphical abstract

Keywords

CNV / disease gene / complex disease / targeted approach / genome-wide approach / whole exome sequencing

References

[1] Schadt, E. E. (2009) Molecular networks as sensors and drivers of common human diseases. Nature, 461, 218–223

[2] Goh, K. I., Cusick, M. E., Valle, D., Childs, B., Vidal, M. and Barabási, A. L. (2007) The human disease network. Proc. Natl. Acad. Sci. USA, 104, 8685–8690

[3] Davies, R. J., Miller, R. and Coleman, N. (2005) Colorectal cancer screening: prospects for molecular stool analysis. Nat. Rev. Cancer, 5, 199–209

[4] Beckmann, J. S., Estivill, X. and Antonarakis, S. E. (2007) Copy number variants and genetic traits: closer to the resolution of phenotypic to genotypic variability. Nat. Rev. Genet., 8, 639–646

[5] Beroukhim, R., Mermel, C. H., Porter, D., Wei, G., Raychaudhuri, S., Donovan, J., Barretina, J., Boehm, J. S., Dobson, J., Urashima, M., (2010) The landscape of somatic copy-number alteration across human cancers. Nature, 463, 899–905

[6] Ritchie, M. D., Holzinger, E. R., Li, R., Pendergrass, S. A. and Kim, D. (2015) Methods of integrating data to uncover genotype-phenotype interactions. Nat. Rev. Genet., 16, 85–97

[7] Ionita-Laza, I., Rogers, A. J., Lange, C., Raby, B. A. and Lee, C. (2009) Genetic association analysis of copy-number variation (CNV) in human disease pathogenesis. Genomics, 93, 22–26

[8] Redon, R., Ishikawa, S., Fitch, K. R., Feuk, L., Perry, G. H., Andrews, T. D., Fiegler, H., Shapero, M. H., Carson, A. R., Chen, W., (2006) Global variation in copy number in the human genome. Nature, 444, 444–454

[9] Freeman, J. L., Perry, G. H., Feuk, L., Redon, R., McCarroll, S. A., Altshuler, D. M., Aburatani, H., Jones, K. W., Tyler-Smith, C., Hurles, M. E., (2006) Copy number variation: new insights in genome diversity. Genome Res., 16, 949–961

[10] Stankiewicz, P. and Lupski, J. R. (2010) Structural variation in the human genome and its role in disease. Annu. Rev. Med., 61, 437–455

[11] Feuk, L., Carson, A. R. and Scherer, S. W. (2006) Structural variation in the human genome. Nat. Rev. Genet., 7, 85–97

[12] Eichler, E. E., Nickerson, D. A., Altshuler, D., Bowcock, A. M., Brooks, L. D., Carter, N. P., Church, D. M., Felsenfeld, A., Guyer, M., Lee, C., (2007) Completing the map of human genetic variation. Nature, 447, 161–165

[13] Li, W. and Olivier, M. (2013) Current analysis platforms and methods for detecting copy number variation. Physiol. Genomics, 45, 1–16

[14] Iafrate, A. J., Feuk, L., Rivera, M. N., Listewnik, M. L., Donahoe, P. K., Qi, Y., Scherer, S. W. and Lee, C. (2004) Detection of large-scale variation in the human genome. Nat. Genet., 36, 949–951

[15] Sebat, J., Lakshmi, B., Troge, J., Alexander, J., Young, J., Lundin, P., Månér, S., Massa, H., Walker, M., Chi, M., (2004) Large-scale copy number polymorphism in the human genome. Science, 305, 525–528

[16] Zhang, J., Feuk, L., Duggan, G. E., Khaja, R. and Scherer, S. W. (2006) Development of bioinformatics resources for display and analysis of copy number and other structural variants in the human genome. Cytogenet. Genome Res., 115, 205–214

[17] Gonzalez, E., Kulkarni, H., Bolivar, H., Mangano, A., Sanchez, R., Catano, G., Nibbs, R., Freedman, B., Marlon P. , Quinones, M., Bamshad, M., (2005) The influence of CCL3L1 gene-containing segmental duplications on HIV-1/AIDS susceptibility. Science, 307, 1434–1440

[18] McCarroll, S. A., Huett, A., Kuballa, P., Chilewski, S. D., Landry, A., Goyette, P., Zody, M. C., Hall, J. L., Brant, S. R., Cho, J. H., (2008) Deletion polymorphism upstream of IRGM associated with altered IRGM expression and Crohn’s disease. Nat. Genet., 40, 1107–1112

[19] Craddock, N., Hurles, M. E., Cardin, N., Pearson, R. D., Plagnol, V., Robson, S., Vukcevic, D., Barnes, C., Conrad, D. F., Giannoulatou, E., (2010) Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls. Nature, 464, 713–720

[20] Aitman, T. J., Dong, R., Vyse, T. J., Norsworthy, P. J., Johnson, M. D., Smith, J., Mangion, J., Roberton-Lowe, C., Marshall, A. J., Petretto, E., (2006) Copy number polymorphism in Fcgr3 predisposes to glomerulonephritis in rats and humans. Nature, 439, 851–855

[21] Cappuzzo, F., Hirsch, F. R., Rossi, E., Bartolini, S., Ceresoli, G. L., Bemis, L., Haney, J., Witta, S., Danenberg, K., Domenichini, I., (2005) Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer. J. Natl. Cancer Inst., 97, 643–655

[22] Glessner, J. T., Connolly, J. J. and Hakonarson, H. (2012) Rare genomic deletions and duplications and their role in neurodevelopmental disorders. Curr. Top. Behav. Neurosci., 12, 345–360

[23] Glessner, J. T., Wang, K., Cai, G., Korvatska, O., Kim, C. E., Wood, S., Zhang, H., Estes, A., Brune, C. W., Bradfield, J. P., (2009) Autism genome-wide copy number variation reveals ubiquitin and neuronal genes. Nature, 459, 569–573

[24] Glessner, J. T., Reilly, M. P., Kim, C. E., Takahashi, N., Albano, A., Hou, C., Bradfield, J. P., Zhang, H., Sleiman, P. M., Flory, J. H., (2010) Strong synaptic transmission impact by copy number variations in schizophrenia. Proc. Natl. Acad. Sci. USA, 107, 10584–10589

[25] Glessner, J. T., Wang, K., Sleiman, P. M., Zhang, H., Kim, C. E., Flory, J. H., Bradfield, J. P., Imielinski, M., Frackelton, E. C., Qiu, H., (2010) Duplication of the SLIT3 locus on 5q35.1 predisposes to major depressive disorder. PLoS One, 5, e15463

[26] Goldmuntz, E., Paluru, P., Glessner, J., Hakonarson, H., Biegel, J. A., White, P. S., Gai, X. and Shaikh, T. H. (2011) Microdeletions and microduplications in patients with congenital heart disease and multiple congenital anomalies. Congenit. Heart Dis., 6, 592–602

[27] Glessner, J. T., Bradfield, J. P., Wang, K., Takahashi, N., Zhang, H., Sleiman, P. M., Mentch, F. D., Kim, C. E., Hou, C., Thomas, K. A., (2010) A genome-wide study reveals copy number variants exclusive to childhood obesity cases. Am. J. Hum. Genet., 87, 661–666

[28] Kuusisto, K. M., Akinrinade, O., Vihinen, M., Kankuri-Tammilehto, M., Laasanen, S. L. and Schleutker, J. (2013) copy number variation analysis in familial BRCA1/2-negative Finnish breast and ovarian cancer PLoS One, 8, e71802

[29] Glessner, J. T., Smith, A. V., Panossian, S., Kim, C. E., Takahashi, N., Thomas, K. A., Wang, F., Seidler, K., Harris, T. B., Launer, L. J., (2013) Copy number variations in alternative splicing gene networks impact lifespan. PLoS One, 8, e53846

[30] Johansson Moller, M., Chaudhary, R., Hellmén, E., Höyheim, B., Chowdhary, B. and Andersson, L. (1996) Pigs with the dominant white coat color phenotype carry a duplication of the KIT gene encoding the mast/stem cell growth factor receptor. Mamm. Genome, 7, 822–830

[31] Norris, B. J. and Whan, V. A. (2008) A gene duplication affecting expression of the ovine ASIP gene is responsible for white and black sheep. Genome Res., 18, 1282–1293

[32] Wright, D., Boije, H., Meadows, J. R. S., Bed’hom, B., Gourichon, D., Vieaud, A., Tixier-Boichard, M., Rubin, C. J., Imsland, F., Hallböök, F., (2009) Copy number variation in intron 1 of SOX5 causes the Pea-comb phenotype in chickens. PLoS Genet., 5, e1000512

[33] Dorshorst, B., Harun-Or-Rashid, M., Bagherpoor, A. J., Rubin, C. J., Ashwell, C., Gourichon, D., Tixier-Boichard, M., Hallböök, F. and Andersson, L. (2015) A genomic duplication is associated with ectopic eomesodermin expression in the embryonic chicken comb and two duplex-comb phenotypes. PLoS Genet., 11, e1004947

[34] Salmon Hillbertz, N. H. C., Isaksson, M., Karlsson, E. K., Hellmén, E., Pielberg, G. R., Savolainen, P., Wade, C. M., von Euler, H., Gustafson, U., Hedhammar, A., (2007) Duplication of FGF3, FGF4, FGF19 and ORAOV1 causes hair ridge and predisposition to dermoid sinus in Ridgeback dogs. Nat. Genet., 39, 1318–1320

[35] Drögemüller, C., Distl, O. and Leeb, T. (2001) Partial deletion of the bovine ED1 gene causes anhidrotic ectodermal dysplasia in cattle. Genome Res., 11, 1699–1705

[36] Capitan, A., Allais-Bonnet, A., Pinton, A., Marquant-Le Guienne, B., Le Bourhis, D., Grohs, C., Bouet, S., Clément, L., Salas-Cortes, L., Venot, E., (2012) A 3.7 Mb deletion encompassing ZEB2 causes a novel polled and multisystemic syndrome in the progeny of a somatic mosaic bull. PLoS One, 7, e49084

[37] Aten, E., White, S. J., Kalf, M. E., Vossen, R. H., Thygesen, H. H., Ruivenkamp, C. A., Kriek, M., Breuning, M. H. and den Dunnen, J. T. (2008) Methods to detect CNVs in the human genome. Cytogenet. Genome Res., 123, 313–321

[38] Kim, T. M., Yim, S. H. and Chung, Y. J. (2008) Copy number variations in the human genome: potential source for individual diversity and disease association studies. Genomics Inform., 6, 1–7

[39] Carter, N. P. (2007) Methods and strategies for analyzing copy number variation using DNA microarrays. Nat. Genet., 39, S16–S21

[40] Buysse, K., Delle Chiaie, B., Van Coster, R., Loeys, B., De Paepe, A., Mortier, G., Speleman, F., Menten, B. (2009) Challenges for CNV interpretation in clinical molecular karyotyping: lessons learned from a 1,001 sample experience. Eur. J. Med. Gene., 52, 398–403

[41] Lucito, R., Healy, J., Alexander, J., Reiner, A., Esposito, D., Chi, M., Rodgers, L., Brady, A., Sebat, J., Troge, J., (2003) Representational oligonucleotide microarray analysis: a high-resolution method to detect genome copy number variation. Genome Res., 13, 2291–2305

[42] Chiang, D. Y., Getz, G., Jaffe, D. B., O’Kelly, M. J., Zhao, X., Carter, S. L., Russ, C., Nusbaum, C., Meyerson, M. and Lander, E. S. (2009) High-resolution mapping of copy-number alterations with massively parallel sequencing. Nat. Methods, 6, 99–103

[43] Geiss, G. K., Bumgarner, R. E., Birditt, B., Dahl, T., Dowidar, N., Dunaway, D. L., Fell, H. P., Ferree, S., George, R. D., Grogan, T., (2008) Direct multiplexed measurement of gene expression with color-coded probe pairs. Nat. Biotechnol., 26, 317–325

[44] Abel, H. J. and Duncavage, E. J. (2013) Detection of structural DNA variation from next generation sequencing data: a review of informatic approaches. Cancer Genet., 206, 432–440

[45] Weksberg, R., Hughes, S., Moldovan, L., Bassett, A. S., Chow, E. W. and Squire, J. A. (2005) A method for accurate detection of genomic microdeletions using real-time quantitative PCR. BMC Genomics, 6, 180

[46] Schouten, J. P., McElgunn, C. J., Waaijer, R., Zwijnenburg, D., Diepvens, F. and Pals, G. (2002) Relative quantification of 40 nucleic acid sequences by multiplex ligation-dependent probe amplification. Nucleic Acids Res., 30, e57

[47] Armour, J. A., Sismani, C., Patsalis, P. C. and Cross, G. (2000) Measurement of locus copy number by hybridisation with amplifiable probes. Nucleic Acids Res., 28, 605–609

[48] Kumps, C., Van Roy, N., Heyrman, L., Goossens, D., Del-Favero, J., Noguera, R., Vandesompele, J., Speleman, F. and De Preter, K. (2010) Multiplex amplicon quantification (MAQ), a fast and efficient method for the simultaneous detection of copy number alterations in neuroblastoma. BMC Genomics, 11, 298

[49] Fernandez-Jimenez, N., Castellanos-Rubio, A., Plaza-Izurieta, L., Gutierrez, G., Irastorza, I., Castaño, L., Vitoria, J. C. and Bilbao, J. R. (2011) Accuracy in copy number calling by qPCR and PRT: a matter of DNA. PLoS One, 6, e28910

[50] Daser, A., Thangavelu, M., Pannell, R., Forster, A., Sparrow, L., Chung, G., Dear, P. H. and Rabbitts, T. H. (2006) Interrogation of genomes by molecular copy-number counting (MCC). Nat. Methods, 3, 447–453

[51] Ceulemans, S., van der Ven, K. and Del-Favero, J. (2012) Targeted screening and validation of copy number variations. Methods Mol. Biol., 838, 311–328

[52] Haraksingh, R. R., Abyzov, A., Gerstein, M., Urban, A. E. and Snyder, M. (2011) Genome-wide mapping of copy number variation in humans: comparative analysis of high resolution array platforms. PLoS One, 6, e27859

[53] Oldridge, D. A., Banerjee, S., Setlur, S. R., Sboner, A. and Demichelis, F. (2010) Optimizing copy number variation analysis using genome-wide short sequence oligonucleotide arrays. Nucleic Acids Res., 38, 3275–3286

[54] Olshen, A. B., Venkatraman, E. S., Lucito, R. and Wigler, M. (2004) Circular binary segmentation for the analysis of array-based DNA copy number data. Biostatistics, 5, 557–572

[55] Hupé P., Stransky, N., Thiery, J. P., Radvanyi, F. and Barillot, E. (2004) Analysis of array CGH data: from signal ratio to gain and loss of DNA regions. Bioinformatics, 20, 3413–3422

[56] Rigaill, G., Hupé P., Almeida, A., La Rosa, P., Meyniel, J. P., Decraene, C. and Barillot, E. (2008) ITALICS: an algorithm for normalization and DNA copy number calling for Affymetrix SNP arrays. Bioinformatics, 24, 768–774

[57] Scharpf, R. B., Ruczinski, I., Carvalho, B., Doan, B., Chakravarti, A. and Irizarry, R. A. (2011) A multilevel model to address batch effects in copy number estimation using SNP arrays. Biostatistics, 12, 33–50

[58] Wang, K., Li, M., Hadley, D., Liu, R., Glessner, J., Grant, S. F., Hakonarson, H. and Bucan, M. (2007) PennCNV: an integrated hidden Markov model designed for high-resolution copy number variation detection in whole-genome SNP genotyping data. Genome Res., 17, 1665–1674

[59] Glessner, J. T., Li, J. and Hakonarson, H. (2013) ParseCNV integrative copy number variation association software with quality tracking. Nucleic Acids Res., 41, e64

[60] Pique-Regi, R., Cáceres, A. and González, J. R. (2010) R-Gada: a fast and flexible pipeline for copy number analysis in association studies. BMC Bioinformatics, 11, 380

[61] Alkan, C., Coe, B. P. and Eichler, E. E. (2011) Genome structural variation discovery and genotyping. Nat. Rev. Genet., 12, 363–376

[62] Meyerson, M., Gabriel, S. and Getz, G. (2010) Advances in understanding cancer genomes through second-generation sequencing. Nat. Rev. Genet., 11, 685–696

[63] Zhao, M., Wang, Q., Wang, Q., Jia, P. and Zhao, Z. (2013) Computational tools for copy number variation (CNV) detection using next-generation sequencing data: fea-tures and perspectives. BMC Bioinformatics, 14 (Suppl 11), S1

[64] Xie, C. and Tammi, M. T. (2009) CNV-seq, a new method to detect copy number variation using high-throughput sequencing. BMC Bioinformatics, 10, 80

[65] Boeva, V., Zinovyev, A., Bleakley, K., Vert, J. P., Janoueix-Lerosey, I., Delattre, O. and Barillot, E. (2011) Control-free calling of copy number alterations in deep-sequencing data using GC-content normalization. Bioinformatics, 27, 268–269

[66] Abyzov, A., Urban, A. E., Snyder, M. and Gerstein, M. (2011) CNVnator: an approach to discover, genotype, and characterize typical and atypical CNVs from family and population genome sequencing. Genome Res., 21, 974–984

[67] Chiang, D. Y., Getz, G., Jaffe, D. B., O’Kelly, M. J. T., Zhao, X., Carter, S. L., Russ, C., Nusbaum, C., Meyerson, M. and Lander, E. S. (2009) High-resolution mapping of copy-number alterations with massively parallel sequencing. Nat. Methods, 6, 99–103

[68] Yoon, S., Xuan, Z., Makarov, V., Ye, K. and Sebat, J. (2009) Sensitive and accurate detection of copy number variants using read depth of coverage. Genome Res., 19, 1586–1592

[69] Chen, K., Wallis, J. W., McLellan, M. D., Larson, D. E., Kalicki, J. M., Pohl, C. S., McGrath, S. D., Wendl, M. C., Zhang, Q., Locke, D. P., (2009) BreakDancer: an algorithm for high-resolution mapping of genomic structural variation. Nat. Methods, 6, 677–681

[70] Sathirapongsasuti, J. F., Lee, H., Horst, B. A., Brunner, G., Cochran, A. J., Binder, S., Quackenbush, J. and Nelson, S. F. (2011) Exome sequencing-based copy-number variation and loss of heterozygosity detection: ExomeCNV. Bioinformatics, 27, 2648–2654

[71] Fromer, M., Moran, J. L., Chambert, K., Banks, E., Bergen, S. E., Ruderfer, D. M., Handsaker, R. E., McCarroll, S. A., O’Donovan, M. C., Owen, M. J., (2012) Discovery and statistical genotyping of copy-number variation from whole-exome sequencing depth. Am. J. Hum. Genet., 91, 597–607

[72] Coin, L. J., Cao, D., Ren, J., Zuo, X., Sun, L., Yang, S., Zhang, X., Cui, Y., Li, Y., Jin, X., (2012) An exome sequencing pipeline for identifying and genotyping common CNVs associated with disease with application to psoriasis. Bioinformatics, 28, i370–i374

[73] Li, A., Liu, Z., Lezon-Geyda, K., Sarkar, S., Lannin, D., Schulz, V., Krop, I., Winer, E., Harris, L. and Tuck, D. (2011) GPHMM: an integrated hidden Markov model for identification of copy number alteration and loss of heterozygosity in complex tumor samples using whole genome SNP arrays. Nucleic Acids Res., 39, 4928–4941

[74] Yu, Z., Liu, Y., Shen, Y., Wang, M. and Li, A. (2014) CLImAT: accurate detection of copy number alteration and loss of heterozygosity in impure and aneuploid tumor samples using whole-genome sequencing data. Bioinformatics, 30, 2576–2583

[75] Iqbal, Z., Caccamo, M., Turner, I., Flicek, P. and McVean, G. (2012) De novo assembly and genotyping of variants using colored de Bruijn graphs. Nat. Genet., 44, 226–232

[76] Nijkamp, J. F., van den Broek, M. A., Geertman, J. M., Reinders, M. J., Daran, J. M. and de Ridder, D. (2012) De novo detection of copy number variation by co-assembly. Bioinformatics, 28, 3195–3202

[77] Beroukhim, R., Getz, G., Nghiemphu, L., Barretina, J., Hsueh, T., Linhart, D., Vivanco, I., Lee, J. C., Huang, J. H., Alexander, S., (2007) Assessing the significance of chromosomal aberrations in cancer: methodology and application to glioma. Proc. Natl. Acad. Sci. USA, 104, 20007–20012

[78] Mermel, C. H., Schumacher, S. E., Hill, B., Meyerson, M. L., Beroukhim, R. and Getz, G. (2011) GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers. Genome Biol., 12, R41

[79] Sanchez-Garcia, F., Akavia, U. D., Mozes, E. and Pe’er, D. (2010) JISTIC: identification of significant targets in cancer. BMC Bioinformatics, 11, 189

[80] Walter, V., Nobel, A.B., and Wright, F.A. (2011) DiNAMIC: A method to identify recurrent DNA copy number aberrations in tumors. Bioinformatics, 27, 678–685

[81] Zhou, X., Liu, J., Wan, X. and Yu, W. (2014) Piecewise-constant and low-rank approximation for identification of recurrent copy number variations. Bioinformatics, 30, 1943–1949

[82] Xi, J. and Li, A. (2016) Discovering recurrent copy number aberrations in complex patterns via non-negative sparse singular value decomposition. IEEE/ACM Trans. Comp. Biol. Bioinfo., (TCBB)., 13, 656–668

[83] Fanciulli, M., Petretto, E. and Aitman, T. J. (2010) Gene copy number variation and common human disease. Clin. Genet., 77, 201–213

[84] Aldred, P. M., Hollox, E. J. and Armour, J. A. (2005) Copy number polymorphism and expression level variation of the human alpha-defensin genes DEFA1 and DEFA3. Hum. Mol. Genet., 14, 2045–2052

[85] Breunis, W. B., van Mirre, E., Bruin, M., Geissler, J., de Boer, M., Peters, M., Roos, D., de Haas, M., Koene, H. R. and Kuijpers, T. W. (2008) Copy number variation of the activating FCGR2C gene predisposes to idiopathic thrombocytopenic purpura. Blood, 111, 1029–1038

[86] Bayés, M., Magano, L. F., Rivera, N., Flores, R. and Pérez Jurado, L. A. (2003) Mutational mechanisms of Williams-Beuren syndrome deletions. Am. J. Hum. Genet., 73, 131–151

[87] Marshall, C. R., Young, E. J., Pani, A. M., Freckmann, M. L., Lacassie, Y., Howald, C., Fitzgerald, K. K., Peippo, M., Morris, C. A., Shane, K., (2008) Infantile spasms is associated with deletion of the MAGI2 gene on chromosome 7q11.23-q21.11. Am. J. Hum. Genet., 83, 106–111

[88] Baldini, A. (2004) DiGeorge syndrome: an update. Curr. Opin. Cardiol., 19, 201–204

[89] Bi, W., Yan, J., Stankiewicz, P., Park, S. S., Walz, K., Boerkoel, C. F., Potocki, L., Shaffer, L. G., Devriendt, K., Nowaczyk, M. J., (2002) Genes in a refined Smith-Magenis syndrome critical deletion interval on chromosome 17p11.2 and the syntenic region of the mouse. Genome Res., 12, 713–728

[90] Potocki, L., Chen, K. S., Park, S. S., Osterholm, D. E., Withers, M. A., Kimonis, V., Summers, A. M., Meschino, W. S., Anyane-Yeboa, K., Kashork, C. D., (2000) Molecular mechanism for duplication 17p11.2 – the homologous recombination reciprocal of the Smith-Magenis microdeletion. Nat. Genet., 24, 84–87

[91] Stone, J. L., O’Donovan, M. C., Gurling, H., Kirov, G. K., Blackwood, D. H. R., Corvin, A., Craddock, N. J., Gill, M., Hultman, C. M., Lichtenstein, P., (2008) Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature, 455, 237–241

[92] Stefansson, H., Rujescu, D., Cichon, S., Pietiläinen, O. P., Ingason, A., Steinberg, S., Fossdal, R., Sigurdsson, E., Sigmundsson, T., Buizer–Voskamp, J. E., (2008) Large recurrent microdeletions associated with schizophrenia. Nature, 455, 232–236

[93] de Vries, B. B., Pfundt, R., Leisink, M., Koolen, D. A., Vissers, L. E., Janssen, I. M., Reijmersdal, S., Nillesen, W. M., Huys, E. H., Leeuw, N., (2005) Diagnostic genome profiling in mental retardation. Am. J. Hum. Genet., 77, 606–616

[94] Friedman, J. M., Baross, Á., Delaney, A. D., Ally, A., Arbour, L., Asano, J., Bailey, D. K., Barber, S., Birch, P., Brown-John, M., (2006) Oligonucleotide microarray analysis of genomic imbalance in children with mental retardation. Am. J. Hum. Genet., 79, 500–513

[95] Marshall, C. R., Noor, A., Vincent, J. B., Lionel, A. C., Feuk, L., Skaug, J., Shago, M., Moessner, R., Pinto, D., Ren, Y., (2008) Structural variation of chromosomes in autism spectrum disorder. Am. J. Hum. Genet., 82, 477–488

[96] Koolen, D. A., Sharp, A. J., Hurst, J. A., Firth, H. V., Knight, S. J., Goldenberg, A., Saugier-Veber, P., Pfundt, R., Vissers, L. E., Destrée, A., (2008) Clinical and molecular delineation of the 17q21.31 microdeletion syndrome. J. Med. Genet., 45, 710–720

[97] Sharp, A. J., Mefford, H. C., Li, K., Baker, C., Skinner, C., Stevenson, R. E., Schroer, R. J., Novara, F., De Gregori, M., Ciccone, R., (2008) A recurrent 15q13.3 microdeletion syndrome associated with mental retardation and seizures. Nat. Genet., 40, 322–328

[98] Mefford, H. C., Sharp, A. J., Baker, C., Itsara, A., Jiang, Z., Buysse, K., Huang, S., Maloney, V. K., Crolla, J. A., Baralle, D., (2008) Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes. N. Engl. J. Med., 359, 1685–1699

[99] Shaffer, L. G., Theisen, A., Bejjani, B. A., Ballif, B. C., Aylsworth, A. S., Lim, C., McDonald, M., Ellison, J. W., Kostiner, D., Saitta, S., (2007) The discovery of microdeletion syndromes in the post-genomic era: review of the methodology and characterization of a new 1q41q42 microdeletion syndrome. Genet. Med., 9, 607–616

[100] Butler, M. G., Meaney, F. J., Palmer, C. G., Opitz, J. M. and Reynolds, J. F. (1986) Clinical and cytogenetic survey of 39 individuals with Prader-Labhart-Willi syndrome. Am. J. Med. Genet., 23, 793–809

[101] Chen, K. S., Manian, P., Koeuth, T., Potocki, L., Zhao, Q., Chinault, A. C., Lee, C. C. and Lupski, J. R. (1997) Homologous recombination of a flanking repeat gene cluster is a mechanism for a common contiguous gene deletion syndrome. Nat. Genet., 17, 154–163

[102] Pérez Jurado, L. A., Peoples, R., Kaplan, P., Hamel, B. C. and Francke, U. (1996) Molecular definition of the chromosome 7 deletion in Williams syndrome and parent-of-origin effects on growth. Am. J. Hum. Genet., 59, 781–792

[103] Edelmann, L., Pandita, R. K., Spiteri, E., Funke, B., Goldberg, R., Palanisamy, N., Chaganti, R. S., Magenis, E., Shprintzen, R. J. and Morrow, B. E. (1999) A common molecular basis for rearrangement disorders on chromosome 22q11. Hum. Mol. Genet., 8, 1157–1167

[104] Bassett, A. S. and Chow, E. W. C. (2008) Schizophrenia and 22q11.2 deletion syndrome. Curr. Psychiatry Rep., 10, 148–157

[105] Walters, R., Jacquemont, S., Valsesia, A., de Smith, A.J., Martinet, D., Andersson, J., Falchi, M., Chen, F., Andrieux, J., Lobbens, S., (2010) A new highly penetrant form of obesity due to deletions on chromosome 16p11. 363 Nature. 463, 671–675

[106] Barbieri, C. E., Baca, S. C., Lawrence, M. S., Demichelis, F., Blattner, M., Theurillat, J. P., White, T. A., Stojanov, P., Van Allen, E., Stransky, N., (2012) Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer. Nat. Genet., 44, 685–689

[107] Kerdpon, D., Sriplung, H. and Kietthubthew, S. (2001) Expression of p53 in oral squamous cell carcinoma and its association with risk habits in southern Thailand. Oral Oncol., 37, 553–557

[108] Topcu, Z., Chiba, I., Fujieda, M., Shibata, T., Ariyoshi, N., Yamazaki, H., Sevgican, F., Muthumala, M., Kobayashi, H. and Kamataki, T. (2002) CYP2A6 gene deletion reduces oral cancer risk in betel quid chewers in Sri Lanka. Carcinogenesis, 23, 595–598

[109] India Project Team of the International Cancer Genome Consortium. (2013) Mutational landscape of gingivo-buccal oral squamous cell carcinoma reveals new recurrently-mutated genes and molecular subgroups. Nat Commun, 4, 2873

[110] Pickering, C. R., Zhang, J., Yoo, S. Y., Bengtsson, L., Moorthy, S., Neskey, D. M., Zhao, M., Ortega Alves, M. V., Chang, K., Drummond, J., (2013) Integrative genomic characterization of oral squamous cell carcinoma identifies frequent somatic drivers. Cancer Discov., 3, 770–781

[111] Stransky, N., Egloff, A. M., Tward, A. D., Kostic, A. D., Cibulskis, K., Sivachenko, A., Kryukov, G. V., Lawrence, M. S., Sougnez, C., McKenna, A., (2011) The mutational landscape of head and neck squamous cell carcinoma. Science, 333, 1157–1160

[112] Salahshourifar, I., Vincent-Chong, V. K., Kallarakkal, T. G. and Zain, R. B. (2014) Genomic DNA copy number alterations from precursor oral lesions to oral squamous cell carcinoma. Oral Oncol., 50, 404–412

[113] Murugan, A. K., Munirajan, A. K. and Tsuchida, N. (2013) Genetic deregulation of the PIK3CA oncogene in oral cancer. Cancer Lett., 338, 193–203

[114] Freier, K., Schwaenen, C., Sticht, C., Flechtenmacher, C., Mühling, J., Hofele, C., Radlwimmer, B., Lichter, P. and Joos, S. (2007) Recurrent FGFR1 amplification and high FGFR1 protein expression in oral squamous cell carcinoma (OSCC). Oral Oncol., 43, 60–66

[115] Martín-Ezquerra, G., Salgado, R., Toll, A., Gilaberte, M., Baró T., Alameda Quitllet, F., Yébenes, M., Solé F., Garcia-Muret, M., Espinet, B., (2010) Multiple genetic copy number alterations in oral squamous cell carcinoma: study of MYC, TP53, CCDN1, EGFR and ERBB2 status in primary and metastatic tumours. Br. J. Dermatol., 163, 1028–1035

[116] Mendes, R. A. (2012) Oncogenic pathways in the development of oral cancer. J. Carcinog. Mutagen., 3, 2

[117] Lee, J. A. and Lupski, J. R. (2006) Genomic rearrangements and gene copy-number alterations as a cause of nervous system disorders. Neuron, 52, 103–121

[118] Cook, E. H. Jr and Scherer, S. W. (2008) Copy-number variations associated with neuropsychiatric conditions. Nature, 455, 919–923

[119] Kalatzis, V. and Antignac, C. (2002) Cystinosis: from gene to disease. Nephrol. Dial. Transplant., 17, 1883–1886

[120] Stahl, E. A., Raychaudhuri, S., Remmers, E. F., Xie, G., Eyre, S., Thomson, B. P., Li, Y., Kurreeman, F. A., Zhernakova, A., Hinks, A., (2010) Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci. Nat. Genet., 42, 508–514

[121] Jung, S. H., Yim, S. H., Hu, H. J., Lee, K. H., Lee, J. H., Sheen, D. H., Lim, M. K., Kim, S. Y., Park, S. W., Kim, S. H., (2014) Genome-wide copy number variation analysis identifies deletion variants associated with ankylosing spondylitis. Arthritis Rheumatol., 66, 2103–2112

[122] Kim, J. H., Jung, S. H., Bae, J. S., Lee, H. S., Yim, S. H., Park, S. Y., Bang, S. Y., Hu, H. J., Shin, H. D., Bae, S. C., (2013) Deletion variants of RABGAP1L, 10q21.3, and C4 are associated with the risk of systemic lupus erythematosus in Korean women. Arthritis Rheum., 65, 1055–1063

[123] Okada, Y., Wu, D., Trynka, G., Raj, T., Terao, C., Ikari, K., Kochi, Y., Ohmura, K., Suzuki, A., Yoshida, S., (2014) Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature, 506, 376–381

[124] de Cid, R., Riveira-Munoz, E., Zeeuwen, P. L., Robarge, J., Liao, W., Dannhauser, E. N., Giardina, E., Stuart, P. E., Nair, R., Helms, C., (2009) Deletion of the late cornified envelope LCE3B and LCE3C genes as a susceptibility factor for psoriasis. Nat. Genet., 41, 211–215

[125] Hüffmeier, U., Bergboer, J. G., Becker, T., Armour, J. A., Traupe, H., Estivill, X., Riveira-Munoz, E., Mössner, R., Reich, K., Kurrat, W., (2010) Replication of LCE3C-LCE3B CNV as a risk factor for psoriasis and analysis of interaction with other genetic risk factors. J. Invest. Dermatol., 130, 979–984

[126] Xu, L., Li, Y., Zhang, X., Sun, H., Sun, D., Jia, X., Shen, C., Zhou, J., Ji, G., Liu, P., (2011) Deletion of LCE3C and LCE3B genes is associated with psoriasis in a northern Chinese population. Br. J. Dermatol., 165, 882–887

[127] Veal, C. D., Reekie, K. E., Lorentzen, J. C., Gregersen, P. K., Padyukov, L. and Brookes, A. J. (2014) A 129-kb deletion on chromosome 12 confers substantial protection against rheumatoid arthritis, implicating the gene SLC2A3. Hum. Mutat., 35, 248–256

[128] Singleton, A. B., Farrer, M., Johnson, J., Singleton, A., Hague, S., Kachergus, J., Hulihan, M., Peuralinna, T., Dutra, A., Nussbaum, R., (2003) α-synuclein locus triplication causes Parkinson’s disease. Science, 302, 841–841

[129] Nagao, Y. (2015) Copy number variations play important roles in heredity of common diseases: a novel method to calculate heritability of a polymorphism. Sci. Rep., 5, 17156

RIGHTS & PERMISSIONS

Higher Education Press and Springer-Verlag GmbH Germany, part of Springer Nature