Genome sequencing in microfabricated high-density picolitre reactors

Marcel Margulies, Michael Egholm, William E. Altman, Said Attiya, Joel S. Bader, Lisa A. Bemben, Jan Berka, Michael S. Braverman, Yi-Ju Chen, Zhoutao Chen, Scott B. Dewell, Lei Du, Joseph M. Fierro, Xavier V. Gomes, Brian C. Godwin, Wen He, Scott Helgesen, Chun He Ho, Gerard P. Irzyk, Szilveszter C. Jando, Maria L. I. Alenquer, Thomas P. Jarvie, Kshama B. Jirage, Jong-Bum Kim, James R. Knight, Janna R. Lanza, John H. Leamon, Steven M. Lefkowitz, Ming Lei, Jing Li, Kenton L. Lohman, Hong Lu, Vinod B. Makhijani, Keith E. McDade, Michael P. McKenna, Eugene W. Myers, Elizabeth Nickerson, John R. Nobile, Ramona Plant, Bernard P. Puc, Michael T. Ronan, George T. Roth, Gary J. Sarkis, Jan Fredrik Simons, John W. Simpson, Maithreyan Srinivasan, Karrie R. Tartaro, Alexander Tomasz, Kari A. Vogt, Greg A. Volkmer, Shally H. Wang, Yong Wang, Michael P. Weiner, Pengguang Yu, Richard F. Begley and Jonathan M. Rothberg ()
Additional contact information
Marcel Margulies: 454 Life Sciences Corp.
Michael Egholm: 454 Life Sciences Corp.
William E. Altman: 454 Life Sciences Corp.
Said Attiya: 454 Life Sciences Corp.
Joel S. Bader: 454 Life Sciences Corp.
Lisa A. Bemben: 454 Life Sciences Corp.
Jan Berka: 454 Life Sciences Corp.
Michael S. Braverman: 454 Life Sciences Corp.
Yi-Ju Chen: 454 Life Sciences Corp.
Zhoutao Chen: 454 Life Sciences Corp.
Scott B. Dewell: 454 Life Sciences Corp.
Lei Du: 454 Life Sciences Corp.
Joseph M. Fierro: 454 Life Sciences Corp.
Xavier V. Gomes: 454 Life Sciences Corp.
Brian C. Godwin: 454 Life Sciences Corp.
Wen He: 454 Life Sciences Corp.
Scott Helgesen: 454 Life Sciences Corp.
Chun He Ho: 454 Life Sciences Corp.
Gerard P. Irzyk: 454 Life Sciences Corp.
Szilveszter C. Jando: 454 Life Sciences Corp.
Maria L. I. Alenquer: 454 Life Sciences Corp.
Thomas P. Jarvie: 454 Life Sciences Corp.
Kshama B. Jirage: 454 Life Sciences Corp.
Jong-Bum Kim: 454 Life Sciences Corp.
James R. Knight: 454 Life Sciences Corp.
Janna R. Lanza: 454 Life Sciences Corp.
John H. Leamon: 454 Life Sciences Corp.
Steven M. Lefkowitz: 454 Life Sciences Corp.
Ming Lei: 454 Life Sciences Corp.
Jing Li: 454 Life Sciences Corp.
Kenton L. Lohman: 454 Life Sciences Corp.
Hong Lu: 454 Life Sciences Corp.
Vinod B. Makhijani: 454 Life Sciences Corp.
Keith E. McDade: 454 Life Sciences Corp.
Michael P. McKenna: 454 Life Sciences Corp.
Eugene W. Myers: University of California
Elizabeth Nickerson: 454 Life Sciences Corp.
John R. Nobile: 454 Life Sciences Corp.
Ramona Plant: 454 Life Sciences Corp.
Bernard P. Puc: 454 Life Sciences Corp.
Michael T. Ronan: 454 Life Sciences Corp.
George T. Roth: 454 Life Sciences Corp.
Gary J. Sarkis: 454 Life Sciences Corp.
Jan Fredrik Simons: 454 Life Sciences Corp.
John W. Simpson: 454 Life Sciences Corp.
Maithreyan Srinivasan: 454 Life Sciences Corp.
Karrie R. Tartaro: 454 Life Sciences Corp.
Alexander Tomasz: The Rockefeller University
Kari A. Vogt: 454 Life Sciences Corp.
Greg A. Volkmer: 454 Life Sciences Corp.
Shally H. Wang: 454 Life Sciences Corp.
Yong Wang: 454 Life Sciences Corp.
Michael P. Weiner: The Rothberg Institute for Childhood Diseases
Pengguang Yu: 454 Life Sciences Corp.
Richard F. Begley: 454 Life Sciences Corp.
Jonathan M. Rothberg: 454 Life Sciences Corp.

Nature, 2005, vol. 437, issue 7057, 376-380

Abstract: Abstract The proliferation of large-scale DNA-sequencing projects in recent years has driven a search for alternative methods to reduce time and cost. Here we describe a scalable, highly parallel sequencing system with raw throughput significantly greater than that of state-of-the-art capillary electrophoresis instruments. The apparatus uses a novel fibre-optic slide of individual wells and is able to sequence 25 million bases, at 99% or better accuracy, in one four-hour run. To achieve an approximately 100-fold increase in throughput over current Sanger sequencing technology, we have developed an emulsion method for DNA amplification and an instrument for sequencing by synthesis using a pyrosequencing protocol optimized for solid support and picolitre-scale volumes. Here we show the utility, throughput, accuracy and robustness of this system by shotgun sequencing and de novo assembly of the Mycoplasma genitalium genome with 96% coverage at 99.96% accuracy in one run of the machine.

Date: 2005
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DOI: 10.1038/nature03959

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