Detection and Interpretation of Genomic Structural Variation in Mammals

Part of the Methods in Molecular Biology book series (MIMB, volume 838)


Structural variation (SV) encompasses diverse types of genomic variants including deletions, duplications, inversions, transpositions, translocations, and complex rearrangements, and is now recognized to be an abundant class of genetic variation in mammals. Different individuals, or strains, of a given species can differ by thousands of variants. However, despite a large number of studies over the past decade and impressive progress on many fronts, there remain significant gaps in our knowledge, particularly in species other than human. Arguably the most relevant among these are genetically tractable models such as mouse, rat, and dog. The emergence of efficient and affordable DNA sequencing technologies presents an opportunity to make rapid progress toward understanding the nature, origin, and function of SV in these, and other, domesticated species. Here, we summarize the current state of knowledge of SV in mammals, with a focus on the similarities and differences between domesticated species and human. We then present methods to identify SV breakpoints from next-generation sequence (NGS) data by paired-end mapping, split-read mapping, and local assembly, and discuss challenges that arise when interpreting these data in lineages with complex breeding histories and incomplete reference genomes. We further describe technical modifications that allow for identification of variants involving repetitive DNA elements such as transposons and segmental duplications. Finally, we explore a few of the key biological insights that can be gained by applying NGS methods to model organisms.

Key words

Structural variation Copy number variation Mammals Model systems Paired-end mapping Split-read mapping Breakpoint assembly Mutation mechanism Next-generation sequencing Genomic rearrangements 


  1. 1.
    Bailey, J. A., Yavor, A. M., Massa, H. F., Trask, B. J., and Eichler, E. E. (2001) Segmental duplications: organization and impact within the current human genome project assembly, Genome Res 11, 1005–1017.PubMedCrossRefGoogle Scholar
  2. 2.
    Marques-Bonet, T., Girirajan, S., and Eichler, E. E. (2009) The origins and impact of primate segmental duplications, Trends Genet 25, 443–454.PubMedCrossRefGoogle Scholar
  3. 3.
    She, X., Cheng, Z., Zollner, S., Church, D. M., and Eichler, E. E. (2008) Mouse segmental duplication and copy number variation, Nat Genet 40, 909–914.PubMedCrossRefGoogle Scholar
  4. 4.
    Liu, G. E., Ventura, M., Cellamare, A., Chen, L., Cheng, Z., Zhu, B., Li, C., Song, J., and Eichler, E. E. (2009) Analysis of recent segmental duplications in the bovine genome, BMC Genomics 10, 571.PubMedCrossRefGoogle Scholar
  5. 5.
    Tuzun, E., Bailey, J. A., and Eichler, E. E. (2004) Recent segmental duplications in the working draft assembly of the brown Norway rat, Genome Res 14, 493–506.PubMedCrossRefGoogle Scholar
  6. 6.
    Nicholas, T. J., Cheng, Z., Ventura, M., Mealey, K., Eichler, E. E., and Akey, J. M. (2009) The genomic architecture of segmental duplications and associated copy number variants in dogs, Genome Res 19, 491–499.PubMedCrossRefGoogle Scholar
  7. 7.
    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.PubMedCrossRefGoogle Scholar
  8. 8.
    Sebat, J., Lakshmi, B., Troge, J., Alexander, J., Young, J., Lundin, P., Maner, S., Massa, H., Walker, M., Chi, M., Navin, N., Lucito, R., Healy, J., Hicks, J., Ye, K., Reiner, A., Gilliam, T. C., Trask, B., Patterson, N., Zetterberg, A., and Wigler, M. (2004) Large-scale copy number polymorphism in the human genome, Science 305, 525–528.PubMedCrossRefGoogle Scholar
  9. 9.
    Feuk, L., Carson, A. R., and Scherer, S. W. (2006) Structural variation in the human genome, Nature Reviews Genetics 7, 85–97.PubMedCrossRefGoogle Scholar
  10. 10.
    Li, J., Jiang, T., Mao, J. H., Balmain, A., Peterson, L., Harris, C., Rao, P. H., Havlak, P., Gibbs, R., and Cai, W. W. (2004) Genomic segmental polymorphisms in inbred mouse strains, Nat Genet 36, 952–954.PubMedCrossRefGoogle Scholar
  11. 11.
    Snijders, A. M., Nowak, N. J., Huey, B., Fridlyand, J., Law, S., Conroy, J., Tokuyasu, T., Demir, K., Chiu, R., Mao, J. H., Jain, A. N., Jones, S. J., Balmain, A., Pinkel, D., and Albertson, D. G. (2005) Mapping segmental and sequence variations among laboratory mice using BAC array CGH, Genome Res 15, 302–311.PubMedCrossRefGoogle Scholar
  12. 12.
    Adams, D. J., Dermitzakis, E. T., Cox, T., Smith, J., Davies, R., Banerjee, R., Bonfield, J., Mullikin, J. C., Chung, Y. J., Rogers, J., and Bradley, A. (2005) Complex haplotypes, copy number polymorphisms and coding variation in two recently divergent mouse strains, Nat Genet 37, 532–536.PubMedCrossRefGoogle Scholar
  13. 13.
    Cutler, G., Marshall, L. A., Chin, N., Baribault, H., and Kassner, P. D. (2007) Significant gene content variation characterizes the genomes of inbred mouse strains, Genome Res 17, 1743–1754.PubMedCrossRefGoogle Scholar
  14. 14.
    Graubert, T. A., Cahan, P., Edwin, D., Selzer, R. R., Richmond, T. A., Eis, P. S., Shannon, W. D., Li, X., McLeod, H. L., Cheverud, J. M., and Ley, T. J. (2007) A high-resolution map of segmental DNA copy number variation in the mouse genome, PLoS Genet 3, e3.PubMedCrossRefGoogle Scholar
  15. 15.
    Cahan, P., Li, Y., Izumi, M., and Graubert, T. A. (2009) The impact of copy number variation on local gene expression in mouse hematopoietic stem and progenitor cells, Nat Genet 41, 430–437.PubMedCrossRefGoogle Scholar
  16. 16.
    Henrichsen, C. N., Vinckenbosch, N., Zollner, S., Chaignat, E., Pradervand, S., Schutz, F., Ruedi, M., Kaessmann, H., and Reymond, A. (2009) Segmental copy number variation shapes tissue transcriptomes, Nat Genet 41, 424–429.PubMedCrossRefGoogle Scholar
  17. 17.
    Akagi, K., Li, J., Stephens, R. M., Volfovsky, N., and Symer, D. E. (2008) Extensive variation between inbred mouse strains due to endogenous L1 retrotransposition, Genome Res 18, 869–880.PubMedCrossRefGoogle Scholar
  18. 18.
    Quinlan, A. R., Clark, R. A., Sokolova, S., Leibowitz, M. L., Zhang, Y., Hurles, M. E., and Hall, I. M. (2010) Genome-wide mapping and assembly of structural variant breakpoints in the mouse genome, Genome Research In Press.Google Scholar
  19. 19.
    Egan, C. M., Sridhar, S., Wigler, M., and Hall, I. M. (2007) Recurrent DNA copy number variation in the laboratory mouse, Nat Genet 39, 1384–1389.PubMedCrossRefGoogle Scholar
  20. 20.
    Guryev, V., Saar, K., Adamovic, T., Verheul, M., van Heesch, S. A., Cook, S., Pravenec, M., Aitman, T., Jacob, H., Shull, J. D., Hubner, N., and Cuppen, E. (2008) Distribution and functional impact of DNA copy number variation in the rat, Nat Genet 40, 538–545.PubMedCrossRefGoogle Scholar
  21. 21.
    Chen, W. K., Swartz, J. D., Rush, L. J., and Alvarez, C. E. (2009) Mapping DNA structural variation in dogs, Genome Res 19, 500–509.PubMedCrossRefGoogle Scholar
  22. 22.
    Liu, G. E., Hou, Y., Zhu, B., Cardone, M. F., Jiang, L., Cellamare, A., Mitra, A., Alexander, L. J., Coutinho, L. L., Dell’aquila, M. E., Gasbarre, L. C., Lacalandra, G., Li, R. W., Matukumalli, L. K., Nonneman, D., Regitano, L. C., Smith, T. P., Song, J., Sonstegard, T. S., Van Tassell, C. P., Ventura, M., Eichler, E. E., McDaneld, T. G., and Keele, J. W. Analysis of copy number variations among diverse cattle breeds, Genome Res.Google Scholar
  23. 23.
    Conrad, D. F., Pinto, D., Redon, R., Feuk, L., Gokcumen, O., Zhang, Y., Aerts, J., Andrews, T. D., Barnes, C., Campbell, P., Fitzgerald, T., Hu, M., Ihm, C. H., Kristiansson, K., Macarthur, D. G., Macdonald, J. R., Onyiah, I., Pang, A. W., Robson, S., Stirrups, K., Valsesia, A., Walter, K., Wei, J., Tyler-Smith, C., Carter, N. P., Lee, C., Scherer, S. W., and Hurles, M. E. (2009) Origins and functional impact of copy number variation in the human genome, Nature.Google Scholar
  24. 24.
    Kidd, J. M., Cooper, G. M., Donahue, W. F., Hayden, H. S., Sampas, N., Graves, T., Hansen, N., Teague, B., Alkan, C., Antonacci, F., Haugen, E., Zerr, T., Yamada, N. A., Tsang, P., Newman, T. L., Tuzun, E., Cheng, Z., Ebling, H. M., Tusneem, N., David, R., Gillett, W., Phelps, K. A., Weaver, M., Saranga, D., Brand, A., Tao, W., Gustafson, E., McKernan, K., Chen, L., Malig, M., Smith, J. D., Korn, J. M., McCarroll, S. A., Altshuler, D. A., Peiffer, D. A., Dorschner, M., Stama-toyannopoulos, J., Schwartz, D., Nickerson, D. A., Mullikin, J. C., Wilson, R. K., Bruhn, L., Olson, M. V., Kaul, R., Smith, D. R., and Eichler, E. E. (2008) Mapping and sequencing of structural variation from eight human genomes, Nature 453, 56–64.PubMedCrossRefGoogle Scholar
  25. 25.
    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., Cho, E. K., Dallaire, S., Freeman, J. L., Gonzalez, J. R., Gratacos, M., Huang, J., Kalaitzopoulos, D., Komura, D., Macdonald, J. R., Marshall, C. R., Mei, R., Montgomery, L., Nishimura, K., Okamura, K., Shen, F., Somerville, M. J., Tchinda, J., Valsesia, A., Woodwark, C., Yang, F., Zhang, J., Zerjal, T., Armengol, L., Conrad, D. F., Estivill, X., Tyler-Smith, C., Carter, N. P., Aburatani, H., Lee, C., Jones, K. W., Scherer, S. W., and Hurles, M. E. (2006) Global variation in copy number in the human genome, Nature 444, 444–454.PubMedCrossRefGoogle Scholar
  26. 26.
    Bentley, D. R., Balasubramanian, S., Swerdlow, H. P., Smith, G. P., Milton, J., Brown, C. G., Hall, K. P., Evers, D. J., Barnes, C. L., Bignell, H. R., Boutell, J. M., Bryant, J., Carter, R. J., Keira Cheetham, R., Cox, A. J., Ellis, D. J., Flatbush, M. R., Gormley, N. A., Humphray, S. J., Irving, L. J., Karbelashvili, M. S., Kirk, S. M., Li, H., Liu, X., Maisinger, K. S., Murray, L. J., Obradovic, B., Ost, T., Parkinson, M. L., Pratt, M. R., Rasolonjatovo, I. M., Reed, M. T., Rigatti, R., Rodighiero, C., Ross, M. T., Sabot, A., Sankar, S. V., Scally, A., Schroth, G. P., Smith, M. E., Smith, V. P., Spiridou, A., Torrance, P. E., Tzonev, S. S., Vermaas, E. H., Walter, K., Wu, X., Zhang, L., Alam, M. D., Anastasi, C., Aniebo, I. C., Bailey, D. M., Bancarz, I. R., Banerjee, S., Barbour, S. G., Baybayan, P. A., Benoit, V. A., Benson, K. F., Bevis, C., Black, P. J., Boodhun, A., Brennan, J. S., Bridgham, J. A., Brown, R. C., Brown, A. A., Buermann, D. H., Bundu, A. A., Burrows, J. C., Carter, N. P., Castillo, N., Chiara, E. C. M., Chang, S., Neil Cooley, R., Crake, N. R., Dada, O. O., Diakoumakos, K. D., Dominguez-Fernandez, B., Earnshaw, D. J., Egbujor, U. C., Elmore, D. W., Etchin, S. S., Ewan, M. R., Fedurco, M., Fraser, L. J., Fuentes Fajardo, K. V., Scott Furey, W., George, D., Gietzen, K. J., Goddard, C. P., Golda, G. S., Granieri, P. A., Green, D. E., Gustafson, D. L., Hansen, N. F., Harnish, K., Haudenschild, C. D., Heyer, N. I., Hims, M. M., Ho, J. T., Horgan, A. M., Hoschler, K., Hurwitz, S., Ivanov, D. V., Johnson, M. Q., James, T., Huw Jones, T. A., Kang, G. D., Kerelska, T. H., Kersey, A. D., Khrebtukova, I., Kindwall, A. P., Kingsbury, Z., Kokko-Gonzales, P. I., Kumar, A., Laurent, M. A., Lawley, C. T., Lee, S. E., Lee, X., Liao, A. K., Loch, J. A., Lok, M., Luo, S., Mammen, R. M., Martin, J. W., McCauley, P. G., McNitt, P., Mehta, P., Moon, K. W., Mullens, J. W., Newington, T., Ning, Z., Ling Ng, B., Novo, S. M., O’Neill, M. J., Osborne, M. A., Osnowski, A., Ostadan, O., Paraschos, L. L., Pickering, L., Pike, A. C., Chris Pinkard, D., Pliskin, D. P., Podhasky, J., Quijano, V. J., Raczy, C., Rae, V. H., Rawlings, S. R., Chiva Rodriguez, A., Roe, P. M., Rogers, J., Rogert Bacigalupo, M. C., Romanov, N., Romieu, A., Roth, R. K., Rourke, N. J., Ruediger, S. T., Rusman, E., Sanches-Kuiper, R. M., Schenker, M. R., Seoane, J. M., Shaw, R. J., Shiver, M. K., Short, S. W., Sizto, N. L., Sluis, J. P., Smith, M. A., Ernest Sohna Sohna, J., Spence, E. J., Stevens, K., Sutton, N., Szajkowski, L., Tregidgo, C. L., Turcatti, G., Vandevondele, S., Verhovsky, Y., Virk, S. M., Wakelin, S., Walcott, G. C., Wang, J., Worsley, G. J., Yan, J., Yau, L., Zuerlein, M., Mullikin, J. C., Hurles, M. E., McCooke, N. J., West, J. S., Oaks, F. L., Lundberg, P. L., Klenerman, D., Durbin, R., and Smith, A. J. (2008) Accurate whole human genome sequencing using reversible terminator chemistry, Nature 456, 53–59.PubMedCrossRefGoogle Scholar
  27. 27.
    Wang, J., Wang, W., Li, R., Li, Y., Tian, G., Goodman, L., Fan, W., Zhang, J., Li, J., Guo, Y., Feng, B., Li, H., Lu, Y., Fang, X., Liang, H., Du, Z., Li, D., Zhao, Y., Hu, Y., Yang, Z., Zheng, H., Hellmann, I., Inouye, M., Pool, J., Yi, X., Zhao, J., Duan, J., Zhou, Y., Qin, J., Ma, L., Li, G., Zhang, G., Yang, B., Yu, C., Liang, F., Li, W., Li, S., Ni, P., Ruan, J., Li, Q., Zhu, H., Liu, D., Lu, Z., Li, N., Guo, G., Ye, J., Fang, L., Hao, Q., Chen, Q., Liang, Y., Su, Y., San, A., Ping, C., Yang, S., Chen, F., Li, L., Zhou, K., Ren, Y., Yang, L., Gao, Y., Yang, G., Li, Z., Feng, X., Kristiansen, K., Wong, G. K., Nielsen, R., Durbin, R., Bolund, L., Zhang, X., and Yang, H. (2008) The diploid genome sequence of an Asian individual, Nature 456, 60–65.PubMedCrossRefGoogle Scholar
  28. 28.
    Ahn, S. M., Kim, T. H., Lee, S., Kim, D., Ghang, H., Kim, B. C., Kim, S. Y., Kim, W. Y., Kim, C., Park, D., Lee, Y. S., Kim, S., Reja, R., Jho, S., Kim, C. G., Cha, J. Y., Kim, K. H., Lee, B., Bhak, J., and Kim, S. J. (2009) The first Korean genome sequence and analysis: Full genome sequencing for a socio-ethnic group, Genome Res.Google Scholar
  29. 29.
    Hormozdiari, F., Alkan, C., Eichler, E. E., and Sahinalp, S. C. (2009) Combinatorial algorithms for structural variation detection in high-throughput sequenced genomes, Genome Res 19, 1270–1278.PubMedCrossRefGoogle Scholar
  30. 30.
    McKernan, K. J., Peckham, H. E., Costa, G. L., McLaughlin, S. F., Fu, Y., Tsung, E. F., Clouser, C. R., Duncan, C., Ichikawa, J. K., Lee, C. C., Zhang, Z., Ranade, S. S., Dimalanta, E. T., Hyland, F. C., Sokolsky, T. D., Zhang, L., Sheridan, A., Fu, H., Hendrickson, C. L., Li, B., Kotler, L., Stuart, J. R., Malek, J. A., Manning, J. M., Antipova, A. A., Perez, D. S., Moore, M. P., Hayashibara, K. C., Lyons, M. R., Beaudoin, R. E., Coleman, B. E., Laptewicz, M. W., Sannicandro, A. E., Rhodes, M. D., Gottimukkala, R. K., Yang, S., Bafna, V., Bashir, A., Macbride, A., Alkan, C., Kidd, J. M., Eichler, E. E., Reese, M. G., De La Vega, F. M., and Blanchard, A. P. (2009) Sequence and structural variation in a human genome uncovered by short-read, massively parallel ligation sequencing using two-base encoding, Genome Res.Google Scholar
  31. 31.
    Kazazian, H. H., Jr. (2004) Mobile elements: drivers of genome evolution, Science 303, 1626–1632.PubMedCrossRefGoogle Scholar
  32. 32.
    Sharp, A. J., Locke, D. P., McGrath, S. D., Cheng, Z., Bailey, J. A., Vallente, R. U., Pertz, L. M., Clark, R. A., Schwartz, S., Segraves, R., Oseroff, V. V., Albertson, D. G., Pinkel, D., and Eichler, E. E. (2005) Segmental duplications and copy-number variation in the human genome, American Journal of Human Genetics 77, 78–88.PubMedCrossRefGoogle Scholar
  33. 33.
    Tuzun, E., Sharp, A. J., Bailey, J. A., Kaul, R., Morrison, V. A., Pertz, L. M., Haugen, E., Hayden, H., Albertson, D., Pinkel, D., Olson, M. V., and Eichler, E. E. (2005) Fine-scale structural variation of the human genome, Nature Genetics 37, 727–732.PubMedCrossRefGoogle Scholar
  34. 34.
    Perry, G. H., Tchinda, J., McGrath, S. D., Zhang, J., Picker, S. R., Caceres, A. M., Iafrate, A. J., Tyler-Smith, C., Scherer, S. W., Eichler, E. E., Stone, A. C., and Lee, C. (2006) Hotspots for copy number variation in chimpanzees and humans, Proc Natl Acad Sci U S A 103, 8006–8011.PubMedCrossRefGoogle Scholar
  35. 35.
    Bourque, G., Pevzner, P. A., and Tesler, G. (2004) Reconstructing the genomic architecture of ancestral mammals: lessons from human, mouse, and rat genomes, Genome Res 14, 507–516.PubMedCrossRefGoogle Scholar
  36. 36.
    Bailey, J. A., Baertsch, R., Kent, W. J., Haussler, D., and Eichler, E. E. (2004) Hotspots of mammalian chromosomal evolution, Genome Biol 5, R23.PubMedCrossRefGoogle Scholar
  37. 37.
    Murphy, W. J., Larkin, D. M., Everts-van der Wind, A., Bourque, G., Tesler, G., Auvil, L., Beever, J. E., Chowdhary, B. P., Galibert, F., Gatzke, L., Hitte, C., Meyers, S. N., Milan, D., Ostrander, E. A., Pape, G., Parker, H. G., Raudsepp, T., Rogatcheva, M. B., Schook, L. B., Skow, L. C., Welge, M., Womack, J. E., O’Brien S, J., Pevzner, P. A., and Lewin, H. A. (2005) Dynamics of mammalian chromosome evolution inferred from multispecies comparative maps, Science 309, 613–617.Google Scholar
  38. 38.
    Lupski, J. R. (2007) Genomic rearrangements and sporadic disease, Nat Genet 39, S43-47.PubMedCrossRefGoogle Scholar
  39. 39.
    Stankiewicz, P., Shaw, C. J., Dapper, J. D., Wakui, K., Shaffer, L. G., Withers, M., Elizondo, L., Park, S. S., and Lupski, J. R. (2003) Genome architecture catalyzes nonrecurrent chromosomal rearrangements, Am J Hum Genet 72, 1101–1116.PubMedCrossRefGoogle Scholar
  40. 40.
    Lee, J. A., Inoue, K., Cheung, S. W., Shaw, C. A., Stankiewicz, P., and Lupski, J. R. (2006) Role of genomic architecture in PLP1 duplication causing Pelizaeus-Merzbacher disease, Hum Mol Genet 15, 2250–2265.PubMedCrossRefGoogle Scholar
  41. 41.
    Bauters, M., Van Esch, H., Friez, M. J., Boespflug-Tanguy, O., Zenker, M., Vianna-Morgante, A. M., Rosenberg, C., Ignatius, J., Raynaud, M., Hollanders, K., Govaerts, K., Vandenreijt, K., Niel, F., Blanc, P., Stevenson, R. E., Fryns, J. P., Marynen, P., Schwartz, C. E., and Froyen, G. (2008) Nonrecurrent MECP2 duplications mediated by genomic architecture-driven DNA breaks and break-induced replication repair, Genome Res 18, 847–858.PubMedCrossRefGoogle Scholar
  42. 42.
    Carvalho, C. M., Zhang, F., Liu, P., Patel, A., Sahoo, T., Bacino, C. A., Shaw, C., Peacock, S., Pursley, A., Tavyev, Y. J., Ramocki, M. B., Nawara, M., Obersztyn, E., Vianna-Morgante, A. M., Stankiewicz, P., Zoghbi, H. Y., Cheung, S. W., and Lupski, J. R. (2009) Complex rearrangements in patients with duplications of MECP2 can occur by fork stalling and template switching, Hum Mol Genet 18, 2188–2203.PubMedCrossRefGoogle Scholar
  43. 43.
    Kim, P. M., Lam, H. Y., Urban, A. E., Korbel, J. O., Affourtit, J., Grubert, F., Chen, X., Weissman, S., Snyder, M., and Gerstein, M. B. (2008) Analysis of copy number variants and segmental duplications in the human genome: Evidence for a change in the process of formation in recent evolutionary history, Genome Res 18, 1865–1874.PubMedCrossRefGoogle Scholar
  44. 44.
    Bailey, J. A., Church, D. M., Ventura, M., Rocchi, M., and Eichler, E. E. (2004) Analysis of segmental duplications and genome assembly in the mouse, Genome Res 14, 789–801.PubMedCrossRefGoogle Scholar
  45. 45.
    Hampton, O. A., Den Hollander, P., Miller, C. A., Delgado, D. A., Li, J., Coarfa, C., Harris, R. A., Richards, S., Scherer, S. E., Muzny, D. M., Gibbs, R. A., Lee, A. V., and Milosavljevic, A. (2009) A sequence-level map of chromosomal breakpoints in the MCF-7 breast cancer cell line yields insights into the evolution of a cancer genome, Genome Res 19, 167–177.PubMedCrossRefGoogle Scholar
  46. 46.
    Bailey, J. A., Gu, Z., Clark, R. A., Reinert, K., Samonte, R. V., Schwartz, S., Adams, M. D., Myers, E. W., Li, P. W., and Eichler, E. E. (2002) Recent segmental duplications in the human genome, Science 297, 1003–1007.PubMedCrossRefGoogle Scholar
  47. 47.
    Church, D. M., Goodstadt, L., Hillier, L. W., Zody, M. C., Goldstein, S., She, X., Bult, C. J., Agarwala, R., Cherry, J. L., DiCuccio, M., Hlavina, W., Kapustin, Y., Meric, P., Maglott, D., Birtle, Z., Marques, A. C., Graves, T., Zhou, S., Teague, B., Potamousis, K., Churas, C., Place, M., Herschleb, J., Runnheim, R., Forrest, D., Amos-Landgraf, J., Schwartz, D. C., Cheng, Z., Lindblad-Toh, K., Eichler, E. E., and Ponting, C. P. (2009) Lineage-specific biology revealed by a finished genome assembly of the mouse, PLoS Biol 7, e1000112.PubMedCrossRefGoogle Scholar
  48. 48.
    Lindblad-Toh, K., Wade, C. M., Mikkelsen, T. S., Karlsson, E. K., Jaffe, D. B., Kamal, M., Clamp, M., Chang, J. L., Kulbokas, E. J., 3rd, Zody, M. C., Mauceli, E., Xie, X., Breen, M., Wayne, R. K., Ostrander, E. A., Ponting, C. P., Galibert, F., Smith, D. R., DeJong, P. J., Kirkness, E., Alvarez, P., Biagi, T., Brockman, W., Butler, J., Chin, C. W., Cook, A., Cuff, J., Daly, M. J., DeCaprio, D., Gnerre, S., Grabherr, M., Kellis, M., Kleber, M., Bardeleben, C., Goodstadt, L., Heger, A., Hitte, C., Kim, L., Koepfli, K. P., Parker, H. G., Pollinger, J. P., Searle, S. M., Sutter, N. B., Thomas, R., Webber, C., Baldwin, J., Abebe, A., Abouelleil, A., Aftuck, L., Ait-Zahra, M., Aldredge, T., Allen, N., An, P., Anderson, S., Antoine, C., Arachchi, H., Aslam, A., Ayotte, L., Bachantsang, P., Barry, A., Bayul, T., Benamara, M., Berlin, A., Bessette, D., Blitshteyn, B., Bloom, T., Blye, J., Boguslavskiy, L., Bonnet, C., Boukhgalter, B., Brown, A., Cahill, P., Calixte, N., Camarata, J., Cheshatsang, Y., Chu, J., Citroen, M., Collymore, A., Cooke, P., Dawoe, T., Daza, R., Decktor, K., DeGray, S., Dhargay, N., Dooley, K., Dorje, P., Dorjee, K., Dorris, L., Duffey, N., Dupes, A., Egbiremolen, O., Elong, R., Falk, J., Farina, A., Faro, S., Ferguson, D., Ferreira, P., Fisher, S., FitzGerald, M., Foley, K., Foley, C., Franke, A., Friedrich, D., Gage, D., Garber, M., Gearin, G., Giannoukos, G., Goode, T., Goyette, A., Graham, J., Grandbois, E., Gyaltsen, K., Hafez, N., Hagopian, D., Hagos, B., Hall, J., Healy, C., Hegarty, R., Honan, T., Horn, A., Houde, N., Hughes, L., Hunnicutt, L., Husby, M., Jester, B., Jones, C., Kamat, A., Kanga, B., Kells, C., Khazanovich, D., Kieu, A. C., Kisner, P., Kumar, M., Lance, K., Landers, T., Lara, M., Lee, W., Leger, J. P., Lennon, N., Leuper, L., LeVine, S., Liu, J., Liu, X., Lokyitsang, Y., Lokyitsang, T., Lui, A., Macdonald, J., Major, J., Marabella, R., Maru, K., Matthews, C., McDonough, S., Mehta, T., Meldrim, J., Melnikov, A., Meneus, L., Mihalev, A., Mihova, T., Miller, K., Mittelman, R., Mlenga, V., Mulrain, L., Munson, G., Navidi, A., Naylor, J., Nguyen, T., Nguyen, N., Nguyen, C., Nicol, R., Norbu, N., Norbu, C., Novod, N., Nyima, T., Olandt, P., O’Neill, B., O’Neill, K., Osman, S., Oyono, L., Patti, C., Perrin, D., Phunkhang, P., Pierre, F., Priest, M., Rachupka, A., Raghuraman, S., Rameau, R., Ray, V., Raymond, C., Rege, F., Rise, C., Rogers, J., Rogov, P., Sahalie, J., Settipalli, S., Sharpe, T., Shea, T., Sheehan, M., Sherpa, N., Shi, J., Shih, D., Sloan, J., Smith, C., Sparrow, T., Stalker, J., Stange-Thomann, N., Stavropoulos, S., Stone, C., Stone, S., Sykes, S., Tchuinga, P., Tenzing, P., Tesfaye, S., Thoulutsang, D., Thoulutsang, Y., Topham, K., Topping, I., Tsamla, T., Vassiliev, H., Venkataraman, V., Vo, A., Wangchuk, T., Wangdi, T., Weiand, M., Wilkinson, J., Wilson, A., Yadav, S., Yang, S., Yang, X., Young, G., Yu, Q., Zainoun, J., Zembek, L., Zimmer, A., and Lander, E. S. (2005) Genome sequence, comparative analysis and haplotype structure of the domestic dog, Nature 438, 803–819.Google Scholar
  49. 49.
    Xing, J., Zhang, Y., Han, K., Salem, A. H., Sen, S. K., Huff, C. D., Zhou, Q., Kirkness, E. F., Levy, S., Batzer, M. A., and Jorde, L. B. (2009) Mobile elements create structural variation: analysis of a complete human genome, Genome Res 19, 1516–1526.PubMedCrossRefGoogle Scholar
  50. 50.
    Cordaux, R., and Batzer, M. A. (2009) The impact of retrotransposons on human genome evolution, Nat Rev Genet 10, 691–703.PubMedCrossRefGoogle Scholar
  51. 51.
    Bailey, J. A., Liu, G., and Eichler, E. E. (2003) An Alu transposition model for the origin and expansion of human segmental duplications, Am J Hum Genet 73, 823–834.PubMedCrossRefGoogle Scholar
  52. 52.
    Lee, J. A., Carvalho, C. M., and Lupski, J. R. (2007) A DNA replication mechanism for generating nonrecurrent rearrangements associated with genomic disorders, Cell 131, 1235–1247.PubMedCrossRefGoogle Scholar
  53. 53.
    Hastings, P. J., Ira, G., and Lupski, J. R. (2009) A microhomology-mediated break-induced replication model for the origin of human copy number variation, PLoS Genet 5, e1000327.PubMedCrossRefGoogle Scholar
  54. 54.
    Wade, C. M., and Daly, M. J. (2005) Genetic variation in laboratory mice, Nat Genet 37, 1175–1180.PubMedCrossRefGoogle Scholar
  55. 55.
    Wade, C. M., Kulbokas, E. J., 3rd, Kirby, A. W., Zody, M. C., Mullikin, J. C., Lander, E. S., Lindblad-Toh, K., and Daly, M. J. (2002) The mosaic structure of variation in the laboratory mouse genome, Nature 420, 574–578.PubMedCrossRefGoogle Scholar
  56. 56.
    Saar, K., Beck, A., Bihoreau, M. T., Birney, E., Brocklebank, D., Chen, Y., Cuppen, E., Demonchy, S., Dopazo, J., Flicek, P., Foglio, M., Fujiyama, A., Gut, I. G., Gauguier, D., Guigo, R., Guryev, V., Heinig, M., Hummel, O., Jahn, N., Klages, S., Kren, V., Kube, M., Kuhl, H., Kuramoto, T., Kuroki, Y., Lechner, D., Lee, Y. A., Lopez-Bigas, N., Lathrop, G. M., Mashimo, T., Medina, I., Mott, R., Patone, G., Perrier-Cornet, J. A., Platzer, M., Pravenec, M., Reinhardt, R., Sakaki, Y., Schilhabel, M., Schulz, H., Serikawa, T., Shikhagaie, M., Tatsumoto, S., Taudien, S., Toyoda, A., Voigt, B., Zelenika, D., Zimdahl, H., and Hubner, N. (2008) SNP and haplotype mapping for genetic analysis in the rat, Nat Genet 40, 560–566.PubMedCrossRefGoogle Scholar
  57. 57.
    Medvedev, P., Stanciu, M., and Brudno, M. (2009) Computational methods for discovering structural variation with next-generation sequencing, Nat Methods 6, S13-S20.PubMedCrossRefGoogle Scholar
  58. 58.
    Du, J., Bjornson, R. D., Zhang, Z. D., Kong, Y., Snyder, M., and Gerstein, M. B. (2009) Integrating sequencing technologies in personal genomics: optimal low cost reconstruction of structural variants, PLoS Comput Biol 5, e1000432.PubMedCrossRefGoogle Scholar
  59. 59.
    Bashir, A., Volik, S., Collins, C., Bafna, V., and Raphael, B. J. (2008) Evaluation of paired-end sequencing strategies for detection of genome rearrangements in cancer, PLoS Comput Biol 4, e1000051.PubMedCrossRefGoogle Scholar
  60. 60.
    Alkan, C., Kidd, J. M., Marques-Bonet, T., Aksay, G., Antonacci, F., Hormozdiari, F., Kitzman, J. O., Baker, C., Malig, M., Mutlu, O., Sahinalp, S. C., Gibbs, R. A., and Eichler, E. E. (2009) Personalized copy number and segmental duplication maps using next-generation sequencing, Nat Genet 41, 1061–1067.PubMedCrossRefGoogle Scholar
  61. 61.
    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.Google Scholar
  62. 62.
    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.PubMedCrossRefGoogle Scholar
  63. 63.
    Frazer, K. A., Eskin, E., Kang, H. M., Bogue, M. A., Hinds, D. A., Beilharz, E. J., Gupta, R. V., Montgomery, J., Morenzoni, M. M., Nilsen, G. B., Pethiyagoda, C. L., Stuve, L. L., Johnson, F. M., Daly, M. J., Wade, C. M., and Cox, D. R. (2007) A sequence-based variation map of 8.27 million SNPs in inbred mouse strains, Nature 448, 1050–1053.PubMedCrossRefGoogle Scholar
  64. 64.
    Li, H., and Durbin, R. (2009) Fast and Accurate Short Read Alignment with Burrows-Wheeler Transform, Bioinformatics.Google Scholar
  65. 65.
    Novoalign. (
  66. 66.
  67. 67.
    Li, H., Handsaker, B., Wysoker, A., Fennell, T., Ruan, J., Homer, N., Marth, G., Abecasis, G., and Durbin, R. (2009) The Sequence Alignment/Map format and SAMtools, Bioinformatics 25, 2078–2079.PubMedCrossRefGoogle Scholar
  68. 68.
  69. 69.
    Mills, R. E., Luttig, C. T., Larkins, C. E., Beauchamp, A., Tsui, C., Pittard, W. S., and Devine, S. E. (2006) An initial map of insertion and deletion (INDEL) variation in the human genome, Genome Res 16, 1182–1190.PubMedCrossRefGoogle Scholar
  70. 70.
  71. 71.
    Hastings, P. J., Lupski, J. R., Rosenberg, S. M., and Ira, G. (2009) Mechanisms of change in gene copy number, Nat Rev Genet 10, 551–564.PubMedCrossRefGoogle Scholar
  72. 72.
    Korbel, J. O., Urban, A. E., Affourtit, J. P., Godwin, B., Grubert, F., Simons, J. F., Kim, P. M., Palejev, D., Carriero, N. J., Du, L., Taillon, B. E., Chen, Z., Tanzer, A., Saunders, A. C., Chi, J., Yang, F., Carter, N. P., Hurles, M. E., Weissman, S. M., Harkins, T. T., Gerstein, M. B., Egholm, M., and Snyder, M. (2007) Paired-end mapping reveals extensive structural variation in the human genome, Science 318, 420–426.PubMedCrossRefGoogle Scholar
  73. 73.
    Mamanova, L., Coffey, A. J., Scott, C. E., Kozarewa, I., Turner, E. H., Kumar, A., Howard, E., Shendure, J., and Turner, D. J. Target-enrichment strategies for next-generation sequencing, Nat Methods 7, 111–118.Google Scholar
  74. 74.
    Liang, Q., Conte, N., Skarnes, W. C., and Bradley, A. (2008) Extensive genomic copy number variation in embryonic stem cells, Proc Natl Acad Sci U S A 105, 17453–17456.PubMedCrossRefGoogle Scholar
  75. 75.
    Bruder, C. E., Piotrowski, A., Gijsbers, A. A., Andersson, R., Erickson, S., de Stahl, T. D., Menzel, U., Sandgren, J., von Tell, D., Poplawski, A., Crowley, M., Crasto, C., Partridge, E. C., Tiwari, H., Allison, D. B., Komorowski, J., van Ommen, G. J., Boomsma, D. I., Pedersen, N. L., den Dunnen, J. T., Wirdefeldt, K., and Dumanski, J. P. (2008) Phenotypically concordant and discordant monozygotic twins display different DNA copy-number-variation profiles, Am J Hum Genet 82, 763–771.PubMedCrossRefGoogle Scholar
  76. 76.
    Piotrowski, A., Bruder, C. E., Andersson, R., de Stahl, T. D., Menzel, U., Sandgren, J., Poplawski, A., von Tell, D., Crasto, C., Bogdan, A., Bartoszewski, R., Bebok, Z., Krzyzanowski, M., Jankowski, Z., Partridge, E. C., Komorowski, J., and Dumanski, J. P. (2008) Somatic mosaicism for copy number variation in differentiated human tissues, Hum Mutat 29, 1118–1124.PubMedCrossRefGoogle Scholar
  77. 77.
    Lam, K. W., and Jeffreys, A. J. (2007) Processes of de novo duplication of human alpha-globin genes, Proc Natl Acad Sci U S A 104, 10950–10955.PubMedCrossRefGoogle Scholar
  78. 78.
    Flores, M., Morales, L., Gonzaga-Jauregui, C., Dominguez-Vidana, R., Zepeda, C., Yanez, O., Gutierrez, M., Lemus, T., Valle, D., Avila, M. C., Blanco, D., Medina-Ruiz, S., Meza, K., Ayala, E., Garcia, D., Bustos, P., Gonzalez, V., Girard, L., Tusie-Luna, T., Davila, G., and Palacios, R. (2007) Recurrent DNA inversion rearrangements in the human genome, Proc Natl Acad Sci U S A 104, 6099–6106.PubMedCrossRefGoogle Scholar
  79. 79.
    Takahashi, K., and Yamanaka, S. (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors, Cell 126, 663–676.PubMedCrossRefGoogle Scholar
  80. 80.
    Boland, M. J., Hazen, J. L., Nazor, K. L., Rodriguez, A. R., Gifford, W., Martin, G., Kupriyanov, S., and Baldwin, K. K. (2009) Adult mice generated from induced pluripotent stem cells, Nature 461, 91–94.PubMedCrossRefGoogle Scholar
  81. 81.
    Wernig, M., Lengner, C. J., Hanna, J., Lodato, M. A., Steine, E., Foreman, R., Staerk, J., Markoulaki, S., and Jaenisch, R. (2008) A drug-inducible transgenic system for direct reprogramming of multiple somatic cell types, Nat Biotechnol 26, 916–924.PubMedCrossRefGoogle Scholar
  82. 82.
    Stranger, B. E., Forrest, M. S., Dunning, M., Ingle, C. E., Beazley, C., Thorne, N., Redon, R., Bird, C. P., de Grassi, A., Lee, C., Tyler-Smith, C., Carter, N., Scherer, S. W., Tavare, S., Deloukas, P., Hurles, M. E., and Dermitzakis, E. T. (2007) Relative impact of nucleotide and copy number variation on gene expression phenotypes, Science 315, 848–853.PubMedCrossRefGoogle Scholar
  83. 83.
    Shearin, A. L., and Ostrander, E. A. Leading the way: canine models of genomics and disease, Dis Model Mech 3, 27–34.Google Scholar
  84. 84.
    Iraqi, F. A., Churchill, G., and Mott, R. (2008) The Collaborative Cross, developing a resource for mammalian systems genetics: a status report of the Wellcome Trust cohort, Mamm Genome 19, 379–381.PubMedCrossRefGoogle Scholar
  85. 85.
    Manolio, T. A., Collins, F. S., Cox, N. J., Goldstein, D. B., Hindorff, L. A., Hunter, D. J., McCarthy, M. I., Ramos, E. M., Cardon, L. R., Chakravarti, A., Cho, J. H., Guttmacher, A. E., Kong, A., Kruglyak, L., Mardis, E., Rotimi, C. N., Slatkin, M., Valle, D., Whittemore, A. S., Boehnke, M., Clark, A. G., Eichler, E. E., Gibson, G., Haines, J. L., Mackay, T. F., McCarroll, S. A., and Visscher, P. M. (2009) Finding the missing heritability of complex diseases, Nature 461, 747–753.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Department of Biochemistry and Molecular GeneticsUniversity of Virginia School of MedicineCharlottesvilleUSA
  2. 2.Center for Public Health GenomicsUniversity of VirginiaCharlottesvilleUSA

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