Characterizing and Interpreting Genetic Variation from Personal Genome Sequencing

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

Abstract

Since the completion of the human genome project, there has been enormous progress in the development of novel technologies for DNA sequencing. The advent of next-generation sequencing technologies now makes it possible to sequence an entire human genome in one or a few experiments. As a consequence, several individual human genomes have now been fully sequenced, using different experimental strategies. Although the protocols differ between the various sequencing technologies, the challenges of analyzing the data, calling variation, and interpreting the results are similar for all platforms. Here, we give an overview of the human genome sequencing projects completed to date. The strategies for aligning sequence reads and extracting information about different types of genetic variation from the sequence data are discussed. Identification of structural variation, such as copy number variation and insertion-deletion variants, can be complex, and there are a plethora of algorithms and analysis tools available. We also give an overview of the challenge of interpreting the whole-genome sequence data both from a technical and clinical perspective.

Key words

Copy number variation Indel Personal genomics Whole-genome sequencing 

References

  1. 1.
    DeLisi, C. (2008) Meetings that changed the world: Santa Fe 1986: Human genome baby-steps, Nature 455, 876–877.PubMedCrossRefGoogle Scholar
  2. 2.
    Lander, E. S., Linton, L. M., Birren, B., Nusbaum, C., Zody, M. C., Baldwin, J., Devon, K., Dewar, K., Doyle, M., FitzHugh, W., Funke, R., Gage, D., Harris, K., Heaford, A., Howland, J., Kann, L., Lehoczky, J., LeVine, R., McEwan, P., McKernan, K., Meldrim, J., Mesirov, J. P., Miranda, C., Morris, W., Naylor, J., Raymond, C., Rosetti, M., Santos, R., Sheridan, A., Sougnez, C., Stange-Thomann, N., Stojanovic, N., Subramanian, A., Wyman, D., Rogers, J., Sulston, J., Ainscough, R., Beck, S., Bentley, D., Burton, J., Clee, C., Carter, N., Coulson, A., Deadman, R., Deloukas, P., Dunham, A., Dunham, I., Durbin, R., French, L., Grafham, D., Gregory, S., Hubbard, T., Humphray, S., Hunt, A., Jones, M., Lloyd, C., McMurray, A., Matthews, L., Mercer, S., Milne, S., Mullikin, J. C., Mungall, A., Plumb, R., Ross, M., Shownkeen, R., Sims, S., Waterston, R. H., Wilson, R. K., Hillier, L. W., McPherson, J. D., Marra, M. A., Mardis, E. R., Fulton, L. A., Chinwalla, A. T., Pepin, K. H., Gish, W. R., Chissoe, S. L., Wendl, M. C., Delehaunty, K. D., Miner, T. L., Delehaunty, A., Kramer, J. B., Cook, L. L., Fulton, R. S., Johnson, D. L., Minx, P. J., Clifton, S. W., Hawkins, T., Branscomb, E., Predki, P., Richardson, P., Wenning, S., Slezak, T., Doggett, N., Cheng, J. F., Olsen, A., Lucas, S., Elkin, C., Uberbacher, E., Frazier, M., Gibbs, R. A., Muzny, D. M., Scherer, S. E., Bouck, J. B., Sodergren, E. J., Worley, K. C., Rives, C. M., Gorrell, J. H., Metzker, M. L., Naylor, S. L., Kucherlapati, R. S., Nelson, D. L., Weinstock, G. M., Sakaki, Y., Fujiyama, A., Hattori, M., Yada, T., Toyoda, A., Itoh, T., Kawagoe, C., Watanabe, H., Totoki, Y., Taylor, T., Weissenbach, J., Heilig, R., Saurin, W., Artiguenave, F., Brottier, P., Bruls, T., Pelletier, E., Robert, C., Wincker, P., Smith, D. R., Doucette-Stamm, L., Rubenfield, M., Weinstock, K., Lee, H. M., Dubois, J., Rosenthal, A., Platzer, M., Nyakatura, G., Taudien, S., Rump, A., Yang, H., Yu, J., Wang, J., Huang, G., Gu, J., Hood, L., Rowen, L., Madan, A., Qin, S., Davis, R. W., Federspiel, N. A., Abola, A. P., Proctor, M. J., Myers, R. M., Schmutz, J., Dickson, M., Grimwood, J., Cox, D. R., Olson, M. V., Kaul, R., Shimizu, N., Kawasaki, K., Minoshima, S., Evans, G. A., Athanasiou, M., Schultz, R., Roe, B. A., Chen, F., Pan, H., Ramser, J., Lehrach, H., Reinhardt, R., McCombie, W. R., de la Bastide, M., Dedhia, N., Blocker, H., Hornischer, K., Nordsiek, G., Agarwala, R., Aravind, L., Bailey, J. A., Bateman, A., Batzoglou, S., Birney, E., Bork, P., Brown, D. G., Burge, C. B., Cerutti, L., Chen, H. C., Church, D., Clamp, M., Copley, R. R., Doerks, T., Eddy, S. R., Eichler, E. E., Furey, T. S., Galagan, J., Gilbert, J. G., Harmon, C., Hayashizaki, Y., Haussler, D., Hermjakob, H., Hokamp, K., Jang, W., Johnson, L. S., Jones, T. A., Kasif, S., Kaspryzk, A., Kennedy, S., Kent, W. J., Kitts, P., Koonin, E. V., Korf, I., Kulp, D., Lancet, D., Lowe, T. M., McLysaght, A., Mikkelsen, T., Moran, J. V., Mulder, N., Pollara, V. J., Ponting, C. P., Schuler, G., Schultz, J., Slater, G., Smit, A. F., Stupka, E., Szustakowski, J., Thierry-Mieg, D., Thierry-Mieg, J., Wagner, L., Wallis, J., Wheeler, R., Williams, A., Wolf, Y. I., Wolfe, K. H., Yang, S. P., Yeh, R. F., Collins, F., Guyer, M. S., Peterson, J., Felsenfeld, A., Wetterstrand, K. A., Patrinos, A., Morgan, M. J., de Jong, P., Catanese, J. J., Osoegawa, K., Shizuya, H., Choi, S., and Chen, Y. J. (2001) Initial sequencing and analysis of the human genome, Nature 409, 860–921.Google Scholar
  3. 3.
    Venter, J. C., Adams, M. D., Myers, E. W., Li, P. W., Mural, R. J., Sutton, G. G., Smith, H. O., Yandell, M., Evans, C. A., Holt, R. A., Gocayne, J. D., Amanatides, P., Ballew, R. M., Huson, D. H., Wortman, J. R., Zhang, Q., Kodira, C. D., Zheng, X. H., Chen, L., Skupski, M., Subramanian, G., Thomas, P. D., Zhang, J., Gabor Miklos, G. L., Nelson, C., Broder, S., Clark, A. G., Nadeau, J., McKusick, V. A., Zinder, N., Levine, A. J., Roberts, R. J., Simon, M., Slayman, C., Hunkapiller, M., Bolanos, R., Delcher, A., Dew, I., Fasulo, D., Flanigan, M., Florea, L., Halpern, A., Hannenhalli, S., Kravitz, S., Levy, S., Mobarry, C., Reinert, K., Remington, K., Abu-Threideh, J., Beasley, E., Biddick, K., Bonazzi, V., Brandon, R., Cargill, M., Chandramouliswaran, I., Charlab, R., Chaturvedi, K., Deng, Z., Di Francesco, V., Dunn, P., Eilbeck, K., Evangelista, C., Gabrielian, A. E., Gan, W., Ge, W., Gong, F., Gu, Z., Guan, P., Heiman, T. J., Higgins, M. E., Ji, R. R., Ke, Z., Ketchum, K. A., Lai, Z., Lei, Y., Li, Z., Li, J., Liang, Y., Lin, X., Lu, F., Merkulov, G. V., Milshina, N., Moore, H. M., Naik, A. K., Narayan, V. A., Neelam, B., Nusskern, D., Rusch, D. B., Salzberg, S., Shao, W., Shue, B., Sun, J., Wang, Z., Wang, A., Wang, X., Wang, J., Wei, M., Wides, R., Xiao, C., Yan, C., Yao, A., Ye, J., Zhan, M., Zhang, W., Zhang, H., Zhao, Q., Zheng, L., Zhong, F., Zhong, W., Zhu, S., Zhao, S., Gilbert, D., Baumhueter, S., Spier, G., Carter, C., Cravchik, A., Woodage, T., Ali, F., An, H., Awe, A., Baldwin, D., Baden, H., Barnstead, M., Barrow, I., Beeson, K., Busam, D., Carver, A., Center, A., Cheng, M. L., Curry, L., Danaher, S., Davenport, L., Desilets, R., Dietz, S., Dodson, K., Doup, L., Ferriera, S., Garg, N., Gluecksmann, A., Hart, B., Haynes, J., Haynes, C., Heiner, C., Hladun, S., Hostin, D., Houck, J., Howland, T., Ibegwam, C., Johnson, J., Kalush, F., Kline, L., Koduru, S., Love, A., Mann, F., May, D., McCawley, S., McIntosh, T., McMullen, I., Moy, M., Moy, L., Murphy, B., Nelson, K., Pfannkoch, C., Pratts, E., Puri, V., Qureshi, H., Reardon, M., Rodriguez, R., Rogers, Y. H., Romblad, D., Ruhfel, B., Scott, R., Sitter, C., Smallwood, M., Stewart, E., Strong, R., Suh, E., Thomas, R., Tint, N. N., Tse, S., Vech, C., Wang, G., Wetter, J., Williams, S., Williams, M., Windsor, S., Winn-Deen, E., Wolfe, K., Zaveri, J., Zaveri, K., Abril, J. F., Guigo, R., Campbell, M. J., Sjolander, K. V., Karlak, B., Kejariwal, A., Mi, H., Lazareva, B., Hatton, T., Narechania, A., Diemer, K., Muruganujan, A., Guo, N., Sato, S., Bafna, V., Istrail, S., Lippert, R., Schwartz, R., Walenz, B., Yooseph, S., Allen, D., Basu, A., Baxendale, J., Blick, L., Caminha, M., Carnes-Stine, J., Caulk, P., Chiang, Y. H., Coyne, M., Dahlke, C., Mays, A., Dombroski, M., Donnelly, M., Ely, D., Esparham, S., Fosler, C., Gire, H., Glanowski, S., Glasser, K., Glodek, A., Gorokhov, M., Graham, K., Gropman, B., Harris, M., Heil, J., Henderson, S., Hoover, J., Jennings, D., Jordan, C., Jordan, J., Kasha, J., Kagan, L., Kraft, C., Levitsky, A., Lewis, M., Liu, X., Lopez, J., Ma, D., Majoros, W., McDaniel, J., Murphy, S., Newman, M., Nguyen, T., Nguyen, N., Nodell, M., Pan, S., Peck, J., Peterson, M., Rowe, W., Sanders, R., Scott, J., Simpson, M., Smith, T., Sprague, A., Stockwell, T., Turner, R., Venter, E., Wang, M., Wen, M., Wu, D., Wu, M., Xia, A., Zandieh, A., and Zhu, X. (2001) The sequence of the human genome, Science 291, 1304–1351.Google Scholar
  4. 4.
    Consortium, I. H. G. S. (2004) Finishing the euchromatic sequence of the human genome, Nature 431, 931–945.CrossRefGoogle Scholar
  5. 5.
    Sanger, F., Nicklen, S., and Coulson, A. R. (1977) DNA sequencing with chain-terminating inhibitors, Proc Natl Acad Sci USA 74, 5463–5467.PubMedCrossRefGoogle Scholar
  6. 6.
    Istrail, S., Sutton, G. G., Florea, L., Halpern, A. L., Mobarry, C. M., Lippert, R., Walenz, B., Shatkay, H., Dew, I., Miller, J. R., Flanigan, M. J., Edwards, N. J., Bolanos, R., Fasulo, D., Halldorsson, B. V., Hannenhalli, S., Turner, R., Yooseph, S., Lu, F., Nusskern, D. R., Shue, B. C., Zheng, X. H., Zhong, F., Delcher, A. L., Huson, D. H., Kravitz, S. A., Mouchard, L., Reinert, K., Remington, K. A., Clark, A. G., Waterman, M. S., Eichler, E. E., Adams, M. D., Hunkapiller, M. W., Myers, E. W., and Venter, J. C. (2004) Whole-genome shotgun assembly and comparison of human genome assemblies, Proc Natl Acad Sci USA 101, 1916–1921.PubMedCrossRefGoogle Scholar
  7. 7.
    Eichler, E. E., Clark, R. A., and She, X. (2004) An assessment of the sequence gaps: unfinished business in a finished human genome, Nat Rev Genet 5, 345–354.PubMedCrossRefGoogle Scholar
  8. 8.
    Bovee, D., Zhou, Y., Haugen, E., Wu, Z., Hayden, H. S., Gillett, W., Tuzun, E., Cooper, G. M., Sampas, N., Phelps, K., Levy, R., Morrison, V. A., Sprague, J., Jewett, D., Buckley, D., Subramaniam, S., Chang, J., Smith, D. R., Olson, M. V., Eichler, E. E., and Kaul, R. (2008) Closing gaps in the human genome with fosmid resources generated from multiple individuals, Nat Genet 40, 96–101.PubMedCrossRefGoogle Scholar
  9. 9.
    Levy, S., Sutton, G., Ng, P. C., Feuk, L., Halpern, A. L., Walenz, B. P., Axelrod, N., Huang, J., Kirkness, E. F., Denisov, G., Lin, Y., MacDonald, J. R., Pang, A. W., Shago, M., Stockwell, T. B., Tsiamouri, A., Bafna, V., Bansal, V., Kravitz, S. A., Busam, D. A., Beeson, K. Y., McIntosh, T. C., Remington, K. A., Abril, J. F., Gill, J., Borman, J., Rogers, Y. H., Frazier, M. E., Scherer, S. W., Strausberg, R. L., and Venter, J. C. (2007) The diploid genome sequence of an individual human, PLoS Biol 5, e254.PubMedCrossRefGoogle Scholar
  10. 10.
    Wheeler, D. A., Srinivasan, M., Egholm, M., Shen, Y., Chen, L., McGuire, A., He, W., Chen, Y. J., Makhijani, V., Roth, G. T., Gomes, X., Tartaro, K., Niazi, F., Turcotte, C. L., Irzyk, G. P., Lupski, J. R., Chinault, C., Song, X. Z., Liu, Y., Yuan, Y., Nazareth, L., Qin, X., Muzny, D. M., Margulies, M., Weinstock, G. M., Gibbs, R. A., and Rothberg, J. M. (2008) The complete genome of an individual by massively parallel DNA sequencing, Nature 452, 872–876.PubMedCrossRefGoogle Scholar
  11. 11.
    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
  12. 12.
    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
  13. 13.
    Pang, A. W., MacDonald, J. R., Pinto, D., Wei, J., Rafiq, M. A., Conrad, D. F., Park, H., Hurles, M. E., Lee, C., Venter, J. C., Kirkness, E. F., Levy, S., Feuk, L., and Scherer, S. W. (2010) Towards a comprehensive structural variation map of an individual human genome, Genome Biol 11, R52.PubMedCrossRefGoogle Scholar
  14. 14.
    Ahn, S. M., Kim, T. H., Lee, S., Kim, D., Ghang, H., Kim, D. S., 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 19, 1622–1629.PubMedCrossRefGoogle Scholar
  15. 15.
    Kim, J. I., Ju, Y. S., Park, H., Kim, S., Lee, S., Yi, J. H., Mudge, J., Miller, N. A., Hong, D., Bell, C. J., Kim, H. S., Chung, I. S., Lee, W. C., Lee, J. S., Seo, S. H., Yun, J. Y., Woo, H. N., Lee, H., Suh, D., Kim, H. J., Yavartanoo, M., Kwak, M., Zheng, Y., Lee, M. K., Kim, J. Y., Gokcumen, O., Mills, R. E., Zaranek, A. W., Thakuria, J., Wu, X., Kim, R. W., Huntley, J. J., Luo, S., Schroth, G. P., Wu, T. D., Kim, H., Yang, K. S., Park, W. Y., Church, G. M., Lee, C., Kingsmore, S. F., and Seo, J. S. (2009) A highly annotated whole-genome sequence of a Korean individual, Nature 460, 1011–1015.PubMedGoogle Scholar
  16. 16.
    Schuster, S. C., Miller, W., Ratan, A., Tomsho, L. P., Giardine, B., Kasson, L. R., Harris, R. S., Petersen, D. C., Zhao, F., Qi, J., Alkan, C., Kidd, J. M., Sun, Y., Drautz, D. I., Bouffard, P., Muzny, D. M., Reid, J. G., Nazareth, L. V., Wang, Q., Burhans, R., Riemer, C., Wittekindt, N. E., Moorjani, P., Tindall, E. A., Danko, C. G., Teo, W. S., Buboltz, A. M., Zhang, Z., Ma, Q., Oosthuysen, A., Steenkamp, A. W., Oostuisen, H., Venter, P., Gajewski, J., Zhang, Y., Pugh, B. F., Makova, K. D., Nekrutenko, A., Mardis, E. R., Patterson, N., Pringle, T. H., Chiaromonte, F., Mullikin, J. C., Eichler, E. E., Hardison, R. C., Gibbs, R. A., Harkins, T. T., and Hayes, V. M. (2010) Complete Khoisan and Bantu genomes from southern Africa, Nature 463, 943–947.PubMedCrossRefGoogle Scholar
  17. 17.
    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 19, 1527–1541.PubMedCrossRefGoogle Scholar
  18. 18.
    Consortium, T. I. H. (2003) The International HapMap Project, Nature 426, 789–796.CrossRefGoogle Scholar
  19. 19.
    Drmanac, R., Sparks, A. B., Callow, M. J., Halpern, A. L., Burns, N. L., Kermani, B. G., Carnevali, P., Nazarenko, I., Nilsen, G. B., Yeung, G., Dahl, F., Fernandez, A., Staker, B., Pant, K. P., Baccash, J., Borcherding, A. P., Brownley, A., Cedeno, R., Chen, L., Chernikoff, D., Cheung, A., Chirita, R., Curson, B., Ebert, J. C., Hacker, C. R., Hartlage, R., Hauser, B., Huang, S., Jiang, Y., Karpinchyk, V., Koenig, M., Kong, C., Landers, T., Le, C., Liu, J., McBride, C. E., Morenzoni, M., Morey, R. E., Mutch, K., Perazich, H., Perry, K., Peters, B. A., Peterson, J., Pethiyagoda, C. L., Pothuraju, K., Richter, C., Rosenbaum, A. M., Roy, S., Shafto, J., Sharanhovich, U., Shannon, K. W., Sheppy, C. G., Sun, M., Thakuria, J. V., Tran, A., Vu, D., Zaranek, A. W., Wu, X., Drmanac, S., Oliphant, A. R., Banyai, W. C., Martin, B., Ballinger, D. G., Church, G. M., and Reid, C. A. (2010) Human genome sequencing using unchained base reads on self-assembling DNA nanoarrays, Science 327, 78–81.PubMedCrossRefGoogle Scholar
  20. 20.
    Pushkarev, D., Neff, N. F., and Quake, S. R. (2009) Single-molecule sequencing of an individual human genome, Nat Biotech 27, 847–850.CrossRefGoogle Scholar
  21. 21.
    Roach, J. C., Glusman, G., Smit, A. F., Huff, C. D., Hubley, R., Shannon, P. T., Rowen, L., Pant, K. P., Goodman, N., Bamshad, M., Shendure, J., Drmanac, R., Jorde, L. B., Hood, L., and Galas, D. J. (2010) Analysis of genetic inheritance in a family quartet by whole-genome sequencing, Science 328, 636–639.PubMedCrossRefGoogle Scholar
  22. 22.
    Ley, T. J., Mardis, E. R., Ding, L., Fulton, B., McLellan, M. D., Chen, K., Dooling, D., Dunford-Shore, B. H., McGrath, S., Hickenbotham, M., Cook, L., Abbott, R., Larson, D. E., Koboldt, D. C., Pohl, C., Smith, S., Hawkins, A., Abbott, S., Locke, D., Hillier, L. W., Miner, T., Fulton, L., Magrini, V., Wylie, T., Glasscock, J., Conyers, J., Sander, N., Shi, X., Osborne, J. R., Minx, P., Gordon, D., Chinwalla, A., Zhao, Y., Ries, R. E., Payton, J. E., Westervelt, P., Tomasson, M. H., Watson, M., Baty, J., Ivanovich, J., Heath, S., Shannon, W. D., Nagarajan, R., Walter, M. J., Link, D. C., Graubert, T. A., DiPersio, J. F., and Wilson, R. K. (2008) DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome, Nature 456, 66–72.PubMedCrossRefGoogle Scholar
  23. 23.
    Mardis, E. R., Ding, L., Dooling, D. J., Larson, D. E., McLellan, M. D., Chen, K., Koboldt, D. C., Fulton, R. S., Delehaunty, K. D., McGrath, S. D., Fulton, L. A., Locke, D. P., Magrini, V. J., Abbott, R. M., Vickery, T. L., Reed, J. S., Robinson, J. S., Wylie, T., Smith, S. M., Carmichael, L., Eldred, J. M., Harris, C. C., Walker, J., Peck, J. B., Du, F., Dukes, A. F., Sanderson, G. E., Brummett, A. M., Clark, E., McMichael, J. F., Meyer, R. J., Schindler, J. K., Pohl, C. S., Wallis, J. W., Shi, X., Lin, L., Schmidt, H., Tang, Y., Haipek, C., Wiechert, M. E., Ivy, J. V., Kalicki, J., Elliott, G., Ries, R. E., Payton, J. E., Westervelt, P., Tomasson, M. H., Watson, M. A., Baty, J., Heath, S., Shannon, W. D., Nagarajan, R., Link, D. C., Walter, M. J., Graubert, T. A., DiPersio, J. F., Wilson, R. K., and Ley, T. J. (2009) Recurring Mutations Found by Sequencing an Acute Myeloid Leukemia Genome, N Engl J Med 361, 1058–1066.PubMedCrossRefGoogle Scholar
  24. 24.
    Campbell, P. J., Stephens, P. J., Pleasance, E. D., O’Meara, S., Li, H., Santarius, T., Stebbings, L. A., Leroy, C., Edkins, S., Hardy, C., Teague, J. W., Menzies, A., Goodhead, I., Turner, D. J., Clee, C. M., Quail, M. A., Cox, A., Brown, C., Durbin, R., Hurles, M. E., Edwards, P. A. W., Bignell, G. R., Stratton, M. R., and Futreal, P. A. (2008) Identification of somatically acquired rearrangements in cancer using genome-wide massively parallel paired-end sequencing, Nat Genet 40, 722–729.PubMedCrossRefGoogle Scholar
  25. 25.
    Pleasance, E. D., Stephens, P. J., O‚ÄôMeara, S., McBride, D. J., Meynert, A., Jones, D., Lin, M.-L., Beare, D., Lau, K. W., Greenman, C., Varela, I., Nik-Zainal, S., Davies, H. R., Ordonez, G. R., Mudie, L. J., Latimer, C., Edkins, S., Stebbings, L., Chen, L., Jia, M., Leroy, C., Marshall, J., Menzies, A., Butler, A., Teague, J. W., Mangion, J., Sun, Y. A., McLaughlin, S. F., Peckham, H. E., Tsung, E. F., Costa, G. L., Lee, C. C., Minna, J. D., Gazdar, A., Birney, E., Rhodes, M. D., McKernan, K. J., Stratton, M. R., Futreal, P. A., and Campbell, P. J. (2010) A small-cell lung cancer genome with complex signatures of tobacco exposure, Nature 463, 184–190.Google Scholar
  26. 26.
    Pleasance, E. D., Cheetham, R. K., Stephens, P. J., McBride, D. J., Humphray, S. J., Greenman, C. D., Varela, I., Lin, M.-L., Ordonez, G. R., Bignell, G. R., Ye, K., Alipaz, J., Bauer, M. J., Beare, D., Butler, A., Carter, R. J., Chen, L., Cox, A. J., Edkins, S., Kokko-Gonzales, P. I., Gormley, N. A., Grocock, R. J., Haudenschild, C. D., Hims, M. M., James, T., Jia, M., Kingsbury, Z., Leroy, C., Marshall, J., Menzies, A., Mudie, L. J., Ning, Z., Royce, T., Schulz-Trieglaff, O. B., Spiridou, A., Stebbings, L. A., Szajkowski, L., Teague, J., Williamson, D., Chin, L., Ross, M. T., Campbell, P. J., Bentley, D. R., Futreal, P. A., and Stratton, M. R. (2010) A comprehensive catalogue of somatic mutations from a human cancer genome, Nature 463, 191–196.PubMedCrossRefGoogle Scholar
  27. 27.
    Consortium, T. I. C. G. (2010) International network of cancer genome projects, Nature 464, 993–998.CrossRefGoogle Scholar
  28. 28.
    Gilbert, M. T., Kivisild, T., Gronnow, B., Andersen, P. K., Metspalu, E., Reidla, M., Tamm, E., Axelsson, E., Gotherstrom, A., Campos, P. F., Rasmussen, M., Metspalu, M., Higham, T. F., Schwenninger, J. L., Nathan, R., De Hoog, C. J., Koch, A., Moller, L. N., Andreasen, C., Meldgaard, M., Villems, R., Bendixen, C., and Willerslev, E. (2008) Paleo-Eskimo mtDNA genome reveals matrilineal discontinuity in Greenland, Science 320, 1787–1789.PubMedCrossRefGoogle Scholar
  29. 29.
    Rasmussen, M., Li, Y., Lindgreen, S., Pedersen, J. S., Albrechtsen, A., Moltke, I., Metspalu, M., Metspalu, E., Kivisild, T., Gupta, R., Bertalan, M., Nielsen, K., Gilbert, M. T., Wang, Y., Raghavan, M., Campos, P. F., Kamp, H. M., Wilson, A. S., Gledhill, A., Tridico, S., Bunce, M., Lorenzen, E. D., Binladen, J., Guo, X., Zhao, J., Zhang, X., Zhang, H., Li, Z., Chen, M., Orlando, L., Kristiansen, K., Bak, M., Tommerup, N., Bendixen, C., Pierre, T. L., Gronnow, B., Meldgaard, M., Andreasen, C., Fedorova, S. A., Osipova, L. P., Higham, T. F., Ramsey, C. B., Hansen, T. V., Nielsen, F. C., Crawford, M. H., Brunak, S., Sicheritz-Ponten, T., Villems, R., Nielsen, R., Krogh, A., Wang, J., and Willerslev, E. (2010) Ancient human genome sequence of an extinct Palaeo-Eskimo, Nature 463, 757–762.PubMedCrossRefGoogle Scholar
  30. 30.
    Green, R. E., Malaspinas, A. S., Krause, J., Briggs, A. W., Johnson, P. L., Uhler, C., Meyer, M., Good, J. M., Maricic, T., Stenzel, U., Prufer, K., Siebauer, M., Burbano, H. A., Ronan, M., Rothberg, J. M., Egholm, M., Rudan, P., Brajkovic, D., Kucan, Z., Gusic, I., Wikstrom, M., Laakkonen, L., Kelso, J., Slatkin, M., and Paabo, S. (2008) A complete Neandertal mitochondrial genome sequence determined by high-throughput sequencing, Cell 134, 416–426.PubMedCrossRefGoogle Scholar
  31. 31.
    Green, R. E., Krause, J., Briggs, A. W., Maricic, T., Stenzel, U., Kircher, M., Patterson, N., Li, H., Zhai, W., Fritz, M. H., Hansen, N. F., Durand, E. Y., Malaspinas, A. S., Jensen, J. D., Marques-Bonet, T., Alkan, C., Prufer, K., Meyer, M., Burbano, H. A., Good, J. M., Schultz, R., Aximu-Petri, A., Butthof, A., Hober, B., Hoffner, B., Siegemund, M., Weihmann, A., Nusbaum, C., Lander, E. S., Russ, C., Novod, N., Affourtit, J., Egholm, M., Verna, C., Rudan, P., Brajkovic, D., Kucan, Z., Gusic, I., Doronichev, V. B., Golovanova, L. V., Lalueza-Fox, C., de la Rasilla, M., Fortea, J., Rosas, A., Schmitz, R. W., Johnson, P. L., Eichler, E. E., Falush, D., Birney, E., Mullikin, J. C., Slatkin, M., Nielsen, R., Kelso, J., Lachmann, M., Reich, D., and Paabo, S. (2010) A draft sequence of the Neandertal genome, Science 328, 710–722.PubMedCrossRefGoogle Scholar
  32. 32.
    Green, R. E., Krause, J., Ptak, S. E., Briggs, A. W., Ronan, M. T., Simons, J. F., Du, L., Egholm, M., Rothberg, J. M., Paunovic, M., and Paabo, S. (2006) Analysis of one million base pairs of Neanderthal DNA, Nature 444, 330–336.PubMedCrossRefGoogle Scholar
  33. 33.
    Noonan, J. P., Coop, G., Kudaravalli, S., Smith, D., Krause, J., Alessi, J., Chen, F., Platt, D., Paabo, S., Pritchard, J. K., and Rubin, E. M. (2006) Sequencing and analysis of Neanderthal genomic DNA, Science 314, 1113–1118.PubMedCrossRefGoogle Scholar
  34. 34.
    Burbano, H. A., Hodges, E., Green, R. E., Briggs, A. W., Krause, J., Meyer, M., Good, J. M., Maricic, T., Johnson, P. L. F., Xuan, Z., Rooks, M., Bhattacharjee, A., Brizuela, L., Albert, F. W., de la Rasilla, M., Fortea, J., Rosas, A., Lachmann, M., Hannon, G. J., and Paabo, S. (2010) Targeted Investigation of the Neandertal Genome by Array-Based Sequence Capture, Science 328, 723–725.PubMedCrossRefGoogle Scholar
  35. 35.
    Ng, S. B., Turner, E. H., Robertson, P. D., Flygare, S. D., Bigham, A. W., Lee, C., Shaffer, T., Wong, M., Bhattacharjee, A., Eichler, E. E., Bamshad, M., Nickerson, D. A., and Shendure, J. (2009) Targeted capture and massively parallel sequencing of 12 human exomes, Nature 461, 272–276.PubMedCrossRefGoogle Scholar
  36. 36.
    Ng, P. C., Levy, S., Huang, J., Stockwell, T. B., Walenz, B. P., Li, K., Axelrod, N., Busam, D. A., Strausberg, R. L., and Venter, J. C. (2008) Genetic variation in an individual human exome, PLoS Genet 4, e1000160.PubMedCrossRefGoogle Scholar
  37. 37.
    Ng, S. B., Buckingham, K. J., Lee, C., Bigham, A. W., Tabor, H. K., Dent, K. M., Huff, C. D., Shannon, P. T., Jabs, E. W., Nickerson, D. A., Shendure, J., and Bamshad, M. J. (2010) Exome sequencing identifies the cause of a mendelian disorder, Nat Genet 42, 30–35.PubMedCrossRefGoogle Scholar
  38. 38.
    Choi, M., Scholl, U. I., Ji, W., Liu, T., Tikhonova, I. R., Zumbo, P., Nayir, A., Bakkaloglu, A., Ozen, S., Sanjad, S., Nelson-Williams, C., Farhi, A., Mane, S., and Lifton, R. P. (2009) Genetic diagnosis by whole exome capture and massively parallel DNA ­sequencing, Proc Natl Acad Sci USA 106, 19096–19101.PubMedCrossRefGoogle Scholar
  39. 39.
    Rehman, A. U., Morell, R. J., Belyantseva, I. A., Khan, S. Y., Boger, E. T., Shahzad, M., Ahmed, Z. M., Riazuddin, S., Khan, S. N., and Friedman, T. B. (2010) Targeted capture and next-generation sequencing identifies C9orf75, encoding taperin, as the mutated gene in nonsyndromic deafness DFNB79, Am J Hum Genet 86, 378–388.PubMedCrossRefGoogle Scholar
  40. 40.
    Walsh, T., Shahin, H., Elkan-Miller, T., Lee, M. K., Thornton, A. M., Roeb, W., Abu Rayyan, A., Loulus, S., Avraham, K. B., King, M.-C., and Kanaan, M. Whole Exome Sequencing and Homozygosity Mapping Identify Mutation in the Cell Polarity Protein GPSM2 as the Cause of Nonsyndromic Hearing Loss DFNB82, The American Journal of Human Genetics In Press, Corrected Proof.Google Scholar
  41. 41.
    Lalonde, E., Albrecht, S., Ha, K. C. H., Jacob, K., Bolduc, N., Polychronakos, C., Dechelotte, P., Majewski, J., and Jabado, N. (2010) Unexpected allelic heterogeneity and spectrum of mutations in Fowler syndrome revealed by next-generation exome sequencing, Human Mutation 9999, n/a.Google Scholar
  42. 42.
    Hoischen, A., Gilissen, C., Arts, P., Wieskamp, N., Vliet, W. v. d., Vermeer, S., Steehouwer, M., Vries, P. d., Meijer, R., Seiqueros, J., Knoers, N. V. A. M., Buckley, M. F., Scheffer, H., and Veltman, J. A. (2010) Massively parallel sequencing of ataxia genes after array-based enrichment, Human Mutation 31, 494–499.Google Scholar
  43. 43.
    Li, R., Li, Y., Zheng, H., Luo, R., Zhu, H., Li, Q., Qian, W., Ren, Y., Tian, G., Li, J., Zhou, G., Zhu, X., Wu, H., Qin, J., Jin, X., Li, D., Cao, H., Hu, X., Blanche, H., Cann, H., Zhang, X., Li, S., Bolund, L., Kristiansen, K., Yang, H., Wang, J., and Wang, J. (2010) Building the sequence map of the human pan-genome, Nat Biotech 28, 57–63.CrossRefGoogle Scholar
  44. 44.
    Khaja, R., Zhang, J., MacDonald, J. R., He, Y., Joseph-George, A. M., Wei, J., Rafiq, M. A., Qian, C., Shago, M., Pantano, L., Aburatani, H., Jones, K., Redon, R., Hurles, M., Armengol, L., Estivill, X., Mural, R. J., Lee, C., Scherer, S. W., and Feuk, L. (2006) Genome assembly comparison identifies structural variants in the human genome, Nat Genet 38, 1413–1418.PubMedCrossRefGoogle Scholar
  45. 45.
    Kidd, J. M., Sampas, N., Antonacci, F., Graves, T., Fulton, R., Hayden, H. S., Alkan, C., Malig, M., Ventura, M., Giannuzzi, G., Kallicki, J., Anderson, P., Tsalenko, A., Yamada, N. A., Tsang, P., Kaul, R., Wilson, R. K., Bruhn, L., and Eichler, E. E. (2010) Characterization of missing human genome sequences and copy-number polymorphic insertions, Nat Meth 7, 365–371.CrossRefGoogle Scholar
  46. 46.
    Li, H., Ruan, J., and Durbin, R. (2008) Mapping short DNA sequencing reads and calling variants using mapping quality scores, Genome Res 18, 1851–1858.PubMedCrossRefGoogle Scholar
  47. 47.
    Hillier, L. W., Marth, G. T., Quinlan, A. R., Dooling, D., Fewell, G., Barnett, D., Fox, P., Glasscock, J. I., Hickenbotham, M., Huang, W., Magrini, V. J., Richt, R. J., Sander, S. N., Stewart, D. A., Stromberg, M., Tsung, E. F., Wylie, T., Schedl, T., Wilson, R. K., and Mardis, E. R. (2008) Whole-genome sequencing and variant discovery in C. elegans, Nat Meth 5, 183–188.CrossRefGoogle Scholar
  48. 48.
    Li, H., Handsaker, B., Wysoker, A., Fennell, T., Ruan, J., Homer, N., Marth, G., Abecasis, G., Durbin, R., and Genome Project Data Processing Subgroup. (2009) The Sequence Alignment/Map format and SAMtools, Bioinformatics 25, 2078–2079.CrossRefGoogle Scholar
  49. 49.
    Li, R., Yu, C., Li, Y., Lam, T.-W., Yiu, S.-M., Kristiansen, K., and Wang, J. (2009) SOAP2: an improved ultrafast tool for short read alignment, Bioinformatics 25, 1966–1967.PubMedCrossRefGoogle Scholar
  50. 50.
    Li, R., Li, Y., Kristiansen, K., and Wang, J. (2008) SOAP: short oligonucleotide alignment program, Bioinformatics 24, 713–714.PubMedCrossRefGoogle Scholar
  51. 51.
    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, Nat Genet 37, 727–732.PubMedCrossRefGoogle Scholar
  52. 52.
    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., Stamatoyannopoulos, 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
  53. 53.
    Lee, S., Hormozdiari, F., Alkan, C., and Brudno, M. (2009) MoDIL: detecting small indels from clone-end sequencing with mixtures of distributions, Nat Meth 6, 473–474.CrossRefGoogle Scholar
  54. 54.
    Korbel, J., Abyzov, A., Mu, X., Carriero, N., Cayting, P., Zhang, Z., Snyder, M., and Gerstein, M. (2009) PEMer: a computational framework with simulation-based error models for inferring genomic structural variants from massive paired-end sequencing data, Genome Biology 10, R23.PubMedCrossRefGoogle Scholar
  55. 55.
    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., Shi, X., Fulton, R. S., Ley, T. J., Wilson, R. K., Ding, L., and Mardis, E. R. (2009) BreakDancer: an algorithm for high-resolution mapping of genomic structural variation, Nat Meth 6, 677–681.CrossRefGoogle Scholar
  56. 56.
    Hajirasouliha, I., Hormozdiari, F., Alkan, C., Kidd, J. M., Birol, I., Eichler, E. E., and Sahinalp, S. C. (2010) Detection and characterization of novel sequence insertions using paired-end next-generation sequencing, Bioinformatics 26, 1277–1283.PubMedCrossRefGoogle Scholar
  57. 57.
    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.PubMedCrossRefGoogle Scholar
  58. 58.
    Conrad, D. F., Bird, C., Blackburne, B., Lindsay, S., Mamanova, L., Lee, C., Turner, D. J., and Hurles, M. E. (2010) Mutation spectrum revealed by breakpoint sequencing of human germline CNVs, Nat Genet 42, 385–391.PubMedCrossRefGoogle Scholar
  59. 59.
    Lam, H. Y., Mu, X. J., Stutz, A. M., Tanzer, A., Cayting, P. D., Snyder, M., Kim, P. M., Korbel, J. O., and Gerstein, M. B. (2010) Nucleotide-resolution analysis of structural variants using BreakSeq and a breakpoint library, Nat Biotechnol 28, 47–55.PubMedCrossRefGoogle Scholar
  60. 60.
    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. E., 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
  61. 61.
    Ye, K., Schulz, M. H., Long, Q., Apweiler, R., and Ning, Z. (2009) Pindel: a pattern growth approach to detect break points of large deletions and medium sized insertions from paired-end short reads, Bioinformatics 25, 2865–2871.PubMedCrossRefGoogle Scholar
  62. 62.
    Ameur, A., Wetterbom, A., Feuk, L., and Gyllensten, U. (2010) Global and unbiased detection of splice junctions from RNA-seq data, Genome Biol 11, R34.PubMedCrossRefGoogle Scholar
  63. 63.
    Feuk, L., Carson, A. R., and Scherer, S. W. (2006) Structural variation in the human genome, Nat Rev Genet 7, 85–97.PubMedCrossRefGoogle Scholar
  64. 64.
    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
  65. 65.
    Lupski, J. R., Reid, J. G., Gonzaga-Jauregui, C., Rio Deiros, D., Chen, D. C., Nazareth, L., Bainbridge, M., Dinh, H., Jing, C., Wheeler, D. A., McGuire, A. L., Zhang, F., Stankiewicz, P., Halperin, J. J., Yang, C., Gehman, C., Guo, D., Irikat, R. K., Tom, W., Fantin, N. J., Muzny, D. M., and Gibbs, R. A. Whole-genome sequencing in a patient with Charcot-Marie-Tooth neuropathy, N Engl J Med 362, 1181–1191.Google Scholar
  66. 66.
    Frazer, K. A., Murray, S. S., Schork, N. J., and Topol, E. J. (2009) Human genetic variation and its contribution to complex traits, Nat Rev Genet 10, 241–251.PubMedCrossRefGoogle Scholar
  67. 67.
    Klein, T. E., Chang, J. T., Cho, M. K., Easton, K. L., Fergerson, R., Hewett, M., Lin, Z., Liu, Y., Liu, S., Oliver, D. E., Rubin, D. L., Shafa, F., Stuart, J. M., and Altman, R. B. (2001) Integrating genotype and phenotype information: an overview of the PharmGKB project. Pharmacogenetics Research Network and Knowledge Base, Pharmacogenomics J 1, 167–170.Google Scholar
  68. 68.
    Ng, P. C., Murray, S. S., Levy, S., and Venter, J. C. (2009) An agenda for personalized medicine, Nature 461, 724–726.PubMedCrossRefGoogle Scholar
  69. 69.
    Ashley, E. A., Butte, A. J., Wheeler, M. T., Chen, R., Klein, T. E., Dewey, F. E., Dudley, J. T., Ormond, K. E., Pavlovic, A., Morgan, A. A., Pushkarev, D., Neff, N. F., Hudgins, L., Gong, L., Hodges, L. M., Berlin, D. S., Thorn, C. F., Sangkuhl, K., Hebert, J. M., Woon, M., Sagreiya, H., Whaley, R., Knowles, J. W., Chou, M. F., Thakuria, J. V., Rosenbaum, A. M., Zaranek, A. W., Church, G. M., Greely, H. T., Quake, S. R., and Altman, R. B. (2010) Clinical assessment incorporating a personal genome, Lancet 375, 1525–1535.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Department of Immunology, Genetics and Pathology, Rudbeck LaboratoryUppsala UniversityUppsalaSweden

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