Abstract
Arrays based on single nucleotide polymorphisms (SNPs) have been successful for the large scale discovery of copy number variants (CNVs). However, current CNV calling algorithms still have limitations in detecting CNVs with high specificity and sensitivity, especially in case of small (<100 kb) CNVs. Therefore, this study presents a simple statistical analysis to evaluate CNV calls from SNP arrays in order to improve the noise-robustness of existing CNV calling algorithms. The proposed approach estimates local noise of log R ratios and returns the probability that a certain observation is different from this log R ratio noise level. This probability can be triggered at different thresholds to tailor specificity and/or sensitivity in a flexible way. Moreover, a comparison based on qPCR experiments showed that the proposed noise-robust CNV calls outperformed original ones for multiple threshold values.
Acknowledgement
Hilde Peeters is a Senior Clinical Investigator of The Research Foundation – Flanders (FWO). This study was supported by the “Opening the Future” Leuven University Fund. The script used for the noise-robust CNV assessment is provided with this manuscript.
References
Alkan, C., B. P. Coe and E. E. Eichler (2011): “Genome structural variation discovery and genotyping,” Nat. Rev. Genet., 12, 363–376.10.1038/nrg2958Search in Google Scholar PubMed PubMed Central
Asadollahi, R., B. Oneda, P. Joset, S. Azzarello-Burri, D. Bartholdi, K. Steindl, M. Vincent, J. Cobilanschi, H. Sticht, R. Baldinger, R. Reissmann, I. Sudholt, C. T. Thiel, A. B. Ekici, A. Reis, E. K. Bijlsma, J. Andrieux, A. Dieux, D. FitzPatrick, S. Ritter, A. Baumer, B. Latal, B. Plecko, O. G. Jenni and A. Rauch (2014): “The clinical significance of small copy number variants in neurodevelopmental disorders,” J. Med. Genet., 51, 677–688.10.1136/jmedgenet-2014-102588Search in Google Scholar PubMed PubMed Central
Baross, A., A. D. Delaney, H. I. Li, T. Nayar, S. Flibotte, H. Qian, S. Y. Chan, J. Asano, A. Ally, M. Cao, P. Birch, M. Brown-John, N. Fernandes, A. Go, G. Kennedy, S. Langlois, P. Eydoux, J. M. Friedman and M. A. Marra (2007): “Assessment of algorithms for high throughput detection of genomic copy number variation in oligonucleotide microarray data,” BMC Bioinformatics, 8, 368.10.1186/1471-2105-8-368Search in Google Scholar PubMed PubMed Central
Beckmann, J. S., X. Estivill and S. E. Antonarakis (2007): “Copy number variants and genetic traits: closer to the resolution of phenotypic to genotypic variability,” Nat. Rev. Genet., 8, 639–646.10.1038/nrg2149Search in Google Scholar PubMed
Brady, P. D. and J. R. Vermeesch (2012): “Genomic microarrays: a technology overview,” Prenat. Diagn., 32, 336–343.10.1002/pd.2933Search in Google Scholar PubMed
Claes, P., K. Daniels, M. Walters, J. Clement, D. Vandermeulen and P. Suetens (2012): “Dysmorphometrics: the modelling of morphological abnormalities,” Theor. Biol. Med. Model., 9, 5.10.1186/1742-4682-9-5Search in Google Scholar PubMed PubMed Central
Conrad, D. F., D. Pinto, R. Redon, L. Feuk, O. Gokcumen, Y. Zhang, J. Aerts, T. D. Andrews, C. Barnes, P. Campbell, T. Fitzgerald, M. Hu, C. H. Ihm, K. Kristiansson, D. G. MacArthur, J. R. MacDonald, I. Onyiah, A. W. C. Pang, S. Robson, K. Stirrups, A. Valsesia, K. Walter, J. Wei, C. Tyler-Smith, N. P. Carter, C. Lee, S. W. Scherer and M. E. Hurles (2010): “Origins and functional impact of copy number variation in the human genome,” Nature, 464, 704–712.10.1038/nature08516Search in Google Scholar PubMed PubMed Central
Dellinger, A. E., S. M. Saw, L. K. Goh, M. Seielstad, T. L. Young and Y. J. Li (2010): “Comparative analyses of seven algorithms for copy number variant identification from single nucleotide polymorphism arrays,” Nucleic Acids Res., 38, 1–14.10.1093/nar/gkq040Search in Google Scholar PubMed PubMed Central
Dhami, P., A. J. Coffey, S. Abbs, J. R. Vermeesch, J. P. Dumanski, K. J. Woodward, R. M. Andrews, C. Langford and D. Vetrie (2005): “Exon array CGH: detection of copy-number changes at the resolution of individual exons in the human genome,” Am. J. Hum. Genet., 76, 750–762.10.1086/429588Search in Google Scholar PubMed PubMed Central
Eckel-Passow, J. E., E. J. Atkinson, S. Maharjan, S. L. Kardia and M. de Andrade (2011): “Software comparison for evaluating genomic copy number variation for Affymetrix 6.0 SNP array platform,” BMC Bioinformatics, 12, 220.10.1186/1471-2105-12-220Search in Google Scholar PubMed PubMed Central
Fernandez-Jimenez, N., A. Castellanos-Rubio, L. Plaza-Izurieta, G. Gutierrez, I. Irastorza, L. Castaño, J. C. Vitoria and J. R. Bilbao (2011): “Accuracy in copy number calling by qPCR and PRT: a matter of DNA,” PLoS One, 6, e28910.10.1371/journal.pone.0028910Search in Google Scholar PubMed PubMed Central
Ionita-Laza, I., A. J. Rogers, C. Lange, B. A. Raby and C. Lee (2009): “Genetic association analysis of copy-number variation (CNV) in human disease pathogenesis,” Genomics, 93, 22–26.10.1016/j.ygeno.2008.08.012Search in Google Scholar PubMed PubMed Central
Jiang, L., J. Jiang, J. Yang, X. Liu, J. Wang, H. Wang, X. Ding, J. Liu and Q. Zhang (2013): “Genome-wide detection of copy number variations using high-density SNP genotyping platforms in Holsteins,” BMC Genomics, 14, 131.10.1186/1471-2164-14-131Search in Google Scholar PubMed PubMed Central
Karimpour-Fard, A., L. Dumas, T. Phang, J. M. Sikela and L. E. Hunter (2010): “A survey of analysis software for array-comparative genomic hybridisation studies to detect copy number variation,” Hum. Genomics, 4, 421.10.1186/1479-7364-4-6-421Search in Google Scholar PubMed PubMed Central
Kirov, G., A. J. Pocklington, P. Holmans, D. Ivanov, M. Ikeda, D. Ruderfer, J. Moran, K. Chambert, D. Toncheva, L. Georgieva, D. Grozeva, M. Fjodorova, R. Wollerton, E. Rees, I. Nikolov, L. N. van de Lagemaat, A. Bayés, E. Fernandez, P. I. Olason, Y. Böttcher, N. H. Komiyama, M. O. Collins, J. Choudhary, K. Stefansson, H. Stefansson, S. G. N. Grant, S. Purcell, P. Sklar, M. C. O’Donovan and M. J. Owen (2012): “De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia,” Mol. Psychiatry, 17, 142–153.10.1038/mp.2011.154Search in Google Scholar PubMed PubMed Central
Krumm, N., B. J. O’Roak, E. Karakoc, K. Mohajeri, B. Nelson, L. Vives, S. Jacquemont, J. Munson, R. Bernier and E. E. Eichler (2013): “Transmission disequilibrium of small CNVs in simplex autism,” Am. J. Hum. Genet., 93, 595–606.10.1016/j.ajhg.2013.07.024Search in Google Scholar PubMed PubMed Central
Macé, A., M. A. Tuke, J. S. Beckmann, L. Lin, S. Jacquemont, M. N. Weedon, A. Reymond and Z. Kutalik (2016): “New quality measure for SNP array based CNV detection,” Bioinformatics, 32, 3298–3305.10.1093/bioinformatics/btw477Search in Google Scholar PubMed
Marmarelis, V. Z. (2004): Nonlinear dynamic modeling of physiological systems. John Wiley & Sons.10.1002/9780471679370Search in Google Scholar
McCarthy, S. E., V. Makarov, G. Kirov, A. M. Addington, J. McClellan, S. Yoon, D. O. Perkins, D. E. Dickel, M. Kusenda, O. Krastoshevsky, V. Krause, R. A. Kumar, D. Grozeva, D. Malhotra, T. Walsh, E. H. Zackai, P. Kaplan, J. Ganesh, I. D. Krantz, N. B. Spinner, P. Roccanova, A. Bhandari, K. Pavon, B. Lakshmi, A. Leotta, J. Kendall, Y.-H. Lee, V. Vacic, S. Gary, L. M. Iakoucheva, T. J. Crow, S. L. Christian, J. A. Lieberman, T. S. Stroup, T. Lehtimäki, K. Puura, C. Haldeman-Englert, J. Pearl, M. Goodell, V. L. Willour, P. DeRosse, J. Steele, L. Kassem, J. Wolff, N. Chitkara, F. J. McMahon, A. K. Malhotra, J. B. Potash, T. G. Schulze, M. M. Nöthen, S. Cichon, M. Rietschel, E. Leibenluft, V. Kustanovich, C. M. Lajonchere, J. S. Sutcliffe, D. Skuse, M. Gill, L. Gallagher, N. R. Mendell, N. Craddock, M. J. Owen, M. C. O’Donovan, T. H. Shaikh, E. Susser, L. E. DeLisi, P. F. Sullivan, C. K. Deutsch, J. Rapoport, D. L. Levy, M.-C. King and J. Sebat (2009): “Microduplications of 16p11.2 are associated with schizophrenia,” Nat. Genet., 41, 1223–1227.10.1038/ng.474Search in Google Scholar PubMed PubMed Central
Menten, B., N. Maas, B. Thienpont, K. Buysse, J. Vandesompele, C. Melotte, T. de Ravel, S. Van Vooren, I. Balikova, L. Backx, S. Janssens, A. De Paepe, B. De Moor, Y. Moreau, P. Marynen, J.-P. Fryns, G. Mortier, K. Devriendt, F. Speleman and J. R. Vermeesch (2006): “Emerging patterns of cryptic chromosomal imbalance in patients with idiopathic mental retardation and multiple congenital anomalies: a new series of 140 patients and review of published reports,” J. Med. Genet., 43, 625–633.10.1136/jmg.2005.039453Search in Google Scholar PubMed PubMed Central
Pinto, D., K. Darvishi, X. Shi, D. Rajan, D. Rigler, T. Fitzgerald, A. C. Lionel, B. Thiruvahindrapuram, J. R. Macdonald, R. Mills, A. Prasad, K. Noonan, S. Gribble, E. Prigmore, P. K. Donahoe, R. S. Smith, J. H. Park, M. E. Hurles, N. P. Carter, C. Lee, S. W. Scherer and L. Feuk (2011): “Comprehensive assessment of array-based platforms and calling algorithms for detection of copy number variants,” Nat. Biotechnol., 29, 512–20.10.1038/nbt.1852Search in Google Scholar PubMed PubMed Central
Pinto, D., A. T. Pagnamenta, L. Klei, R. Anney, D. Merico, R. Regan, J. Conroy, T. R. Magalhaes, C. Correia, B. S. Abrahams, J. Almeida, E. Bacchelli, G. D. Bader, A. J. Bailey, G. Baird, A. Battaglia, T. Berney, N. Bolshakova, S. Bölte, P. F. Bolton, T. Bourgeron, S. Brennan, J. Brian, S. E. Bryson, A. R. Carson, G. Casallo, J. Casey, B. H. Y. Chung, L. Cochrane, C. Corsello, E. L. Crawford, A. Crossett, C. Cytrynbaum, G. Dawson, M. de Jonge, R. Delorme, I. Drmic, E. Duketis, F. Duque, A. Estes, P. Farrar, B. A. Fernandez, S. E. Folstein, E. Fombonne, C. M. Freitag, J. Gilbert, C. Gillberg, J. T. Glessner, J. Goldberg, A. Green, J. Green, S. J. Guter, H. Hakonarson, E. A. Heron, M. Hill, R. Holt, J. L. Howe, G. Hughes, V. Hus, R. Igliozzi, C. Kim, S. M. Klauck, A. Kolevzon, O. Korvatska, V. Kustanovich, C. M. Lajonchere, J. A. Lamb, M. Laskawiec, M. Leboyer, A. Le Couteur, B. L. Leventhal, A. C. Lionel, X.-Q. Liu, C. Lord, L. Lotspeich, S. C. Lund, E. Maestrini, W. Mahoney, C. Mantoulan, C. R. Marshall, H. McConachie, C. J. McDougle, J. McGrath, W. M. McMahon, A. Merikangas, O. Migita, N. J. Minshew, G. K. Mirza, J. Munson, S. F. Nelson, C. Noakes, A. Noor, G. Nygren, G. Oliveira, K. Papanikolaou, J. R. Parr, B. Parrini, T. Paton, A. Pickles, M. Pilorge, J. Piven, C. P. Ponting, D. J. Posey, A. Poustka, F. Poustka, A. Prasad, J. Ragoussis, K. Renshaw, J. Rickaby, W. Roberts, K. Roeder, B. Roge, M. L. Rutter, L. J. Bierut, J. P. Rice, J. Salt, K. Sansom, D. Sato, R. Segurado, A. F. Sequeira, L. Senman, N. Shah, V. C. Sheffield, L. Soorya, I. Sousa, O. Stein, N. Sykes, V. Stoppioni, C. Strawbridge, R. Tancredi, K. Tansey, B. Thiruvahindrapduram, A. P. Thompson, S. Thomson, A. Tryfon, J. Tsiantis, H. Van Engeland, J. B. Vincent, F. Volkmar, S. Wallace, K. Wang, Z. Wang, T. H. Wassink, C. Webber, R. Weksberg, K. Wing, K. Wittemeyer, S. Wood, J. Wu, B. L. Yaspan, D. Zurawiecki, L. Zwaigenbaum, J. D. Buxbaum, R. M. Cantor, E. H. Cook, H. Coon, M. L. Cuccaro, B. Devlin, S. Ennis, L. Gallagher, D. H. Geschwind, M. Gill, J. L. Haines, J. Hallmayer, J. Miller, A. P. Monaco, J. I. Nurnberger, A. D. Paterson, M. A. Pericak-Vance, G. D. Schellenberg, P. Szatmari, A. M. Vicente, V. J. Vieland, E. M. Wijsman, S. W. Scherer, J. S. Sutcliffe and C. Betancur (2010): “Functional impact of global rare copy number variation in autism spectrum disorders,” Nature, 466, 368–72.10.1038/nature09146Search in Google Scholar PubMed PubMed Central
Poultney, C. S., A. P. Goldberg, E. Drapeau, Y. Kou, H. Harony-Nicolas, Y. Kajiwara, S. De Rubeis, S. Durand, C. Stevens, K. Rehnström, A. Palotie, M. J. Daly, A. Ma’ayan, M. Fromer and J. D. Buxbaum (2013): “Identification of small exonic CNV from whole-exome sequence data and application to autism spectrum disorder,” Am. J. Hum. Genet., 93, 607–619.10.1016/j.ajhg.2013.09.001Search in Google Scholar PubMed PubMed Central
Qi, Y., X. Zhou, D. Bu, P. Hou, J. Lv and H. Zhang (2016): “Comparison of multiple methods for determination of FCGR3A/B genomic copy numbers in HapMap Asian Populations with two public databases,” Front. Genet., 7, 1–7.10.3389/fgene.2016.00220Search in Google Scholar PubMed PubMed Central
Robin, X., N. Turck, A. Hainard, N. Tiberti, F. Lisacek, J.-C. Sanchez and M. Müller (2011): “pROC: an open-source package for R and S+ to analyze and compare ROC curves,” BMC Bioinformatics, 12, 77.10.1186/1471-2105-12-77Search in Google Scholar PubMed PubMed Central
Seiser, E. L. and F. Innocenti (2015): “Hidden Markov model-based CNV detection algorithms for Illumina genotyping microarrays,” Cancer Inform., 13, 77.10.4137/CIN.S16345Search in Google Scholar PubMed PubMed Central
Valsesia, A., A. Macé, S. Jacquemont, J. S. Beckmann and Z. Kutalik (2013): “The growing importance of CNVs: new insights for detection and clinical interpretation,” Front. Genet., 4, 1–19.10.3389/fgene.2013.00092Search in Google Scholar PubMed PubMed Central
Vandeweyer, G., E. Reyniers, W. Wuyts, L. Rooms and R. F. Kooy (2011): “CNV-WebStore: online CNV analysis, storage and interpretation,” BMC Bioinformatics, 12, 4.10.1186/1471-2105-12-4Search in Google Scholar PubMed PubMed Central
Vermeesch, J. R., P. D. Brady, D. Sanlaville, K. Kok and R. J. Hastings (2012): “Genome-wide arrays: quality criteria and platforms to be used in routine diagnostics,” Hum. Mutat., 33, 906–915.10.1002/humu.22076Search in Google Scholar PubMed
Vermeesch, J. R., H. Fiegler, N. de Leeuw, K. Szuhai, J. Schoumans, R. Ciccone, F. Speleman, A. Rauch, J. Clayton-Smith, C. Van Ravenswaaij, D. Sanlaville, P. C. Patsalis, H. Firth, K. Devriendt and O. Zuffardi (2007): “Guidelines for molecular karyotyping in constitutional genetic diagnosis,” Eur. J. Hum. Genet., 15, 1105–1114.10.1038/sj.ejhg.5201896Search in Google Scholar PubMed
Winchester, L., C. Yau and J. Ragoussis (2009): “Comparing CNV detection methods for SNP arrays,” Brief. Funct. Genomic. Proteomic., 8, 353–366.10.1093/bfgp/elp017Search in Google Scholar PubMed
Zhao, M., Q. Wang, Q. Wang, P. Jia and Z. Zhao (2013): “Computational tools for copy number variation (CNV) detection using next-generation sequencing data: features and perspectives,” BMC Bioinformatics, 14, S1.10.1186/1471-2105-14-S11-S1Search in Google Scholar PubMed PubMed Central
©2018 Walter de Gruyter GmbH, Berlin/Boston