Nature 452, 872-876 (17 April 2008) | doi:10.1038/nature06884; Received 3 December 2007; Accepted 4 March 2008

The complete genome of an individual by massively parallel DNA sequencing

See associated Correspondence: Roche, Nature 453, 281 (May 2008)

David A. Wheeler1,7, Maithreyan Srinivasan2,7, Michael Egholm2,7, Yufeng Shen1,7, Lei Chen1, Amy McGuire3, Wen He2, Yi-Ju Chen2, Vinod Makhijani2, G. Thomas Roth2, Xavier Gomes2, Karrie Tartaro2,8, Faheem Niazi2, Cynthia L. Turcotte2, Gerard P. Irzyk2, James R. Lupski4,5,6, Craig Chinault4, Xing-zhi Song1, Yue Liu1, Ye Yuan1, Lynne Nazareth1, Xiang Qin1, Donna M. Muzny1, Marcel Margulies2, George M. Weinstock1,4, Richard A. Gibbs1,4 & Jonathan M. Rothberg2,8

  1. Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA
  2. 454 Life Sciences, Roche Diagnostics, 20 Commercial Street, Bradford, Connecticut 06405, USA
  3. Center for Ethics and Health Policy, Baylor College of Medicine, One Baylor Plaza, Houston Texas 77030, USA
  4. Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston Texas 77030, USA
  5. Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston Texas 77030, USA
  6. Texas Children's Hospital, Texas Medical Center, Houston, Texas 77030, USA
  7. These authors contributed equally to this work.
  8. Present addresses: Molecular Imaging Systems, Carestream Health, Inc., 4 Science Park, New Haven, Connecticut 06511, USA (K.T.); Rothberg Institute for Childhood Diseases, 530 Whitfield Street, Guilford, Connecticut 06437, USA (J.M.R.).

Correspondence to: Richard A. Gibbs1,4Jonathan M. Rothberg2,8 Correspondence and requests for materials should be addressed to J.M.R. (Email: jonathan.rothberg@gmail.com) or R.A.G. (Email: agibbs@bcm.tmc.edu).

This article is distributed under the terms of the Creative Commons Attribution-Non-Commercial-Share Alike licence (http://creativecommons.org/licenses/by-nc-sa/3.0/), which permits distribution, and reproduction in any medium, provided the original author and source are credited. This licence does not permit commercial exploitation, and derivative works must be licensed under the same or similar licence.

The association of genetic variation with disease and drug response, and improvements in nucleic acid technologies, have given great optimism for the impact of 'genomic medicine'. However, the formidable size of the diploid human genome1, approximately 6 gigabases, has prevented the routine application of sequencing methods to deciphering complete individual human genomes. To realize the full potential of genomics for human health, this limitation must be overcome. Here we report the DNA sequence of a diploid genome of a single individual, James D. Watson, sequenced to 7.4-fold redundancy in two months using massively parallel sequencing in picolitre-size reaction vessels. This sequence was completed in two months at approximately one-hundredth of the cost of traditional capillary electrophoresis methods. Comparison of the sequence to the reference genome led to the identification of 3.3 million single nucleotide polymorphisms, of which 10,654 cause amino-acid substitution within the coding sequence. In addition, we accurately identified small-scale (2–40,000 base pair (bp)) insertion and deletion polymorphism as well as copy number variation resulting in the large-scale gain and loss of chromosomal segments ranging from 26,000 to 1.5 million base pairs. Overall, these results agree well with recent results of sequencing of a single individual2 by traditional methods. However, in addition to being faster and significantly less expensive, this sequencing technology avoids the arbitrary loss of genomic sequences inherent in random shotgun sequencing by bacterial cloning because it amplifies DNA in a cell-free system. As a result, we further demonstrate the acquisition of novel human sequence, including novel genes not previously identified by traditional genomic sequencing. This is the first genome sequenced by next-generation technologies. Therefore it is a pilot for the future challenges of 'personalized genome sequencing'.


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