Human Genome Sequencing Using Unchained Base Reads on Self-Assembling DNA Nanoarrays

SCIENCE - Published Online November 5, 2009 Science DOI: 10.1126/science.1181498

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Submitted on September 3, 2009
Accepted on October 23, 2009

Radoje Drmanac ^1*, Andrew B. Sparks ¹, Matthew J. Callow ¹, Aaron L. Halpern ¹, Norman L. Burns ¹, Bahram G. Kermani ¹, Paolo Carnevali ¹, Igor Nazarenko ¹, Geoffrey B. Nilsen ¹, George Yeung ¹, Fredrik Dahl ², Andres Fernandez ¹, Bryan Staker ¹, Krishna P. Pant ¹, Jonathan Baccash ¹, Adam P. Borcherding ¹, Anushka Brownley ¹, Ryan Cedeno ¹, Linsu Chen ¹, Dan Chernikoff ¹, Alex Cheung ¹, Razvan Chirita ¹, Benjamin Curson ¹, Jessica C. Ebert ¹, Coleen R. Hacker ¹, Robert Hartlage ¹, Brian Hauser ¹, Steve Huang ¹, Yuan Jiang ¹, Vitali Karpinchyk ¹, Mark Koenig ¹, Calvin Kong ¹, Tom Landers ¹, Catherine Le ¹, Jia Liu ¹, Celeste E. McBride ¹, Matt Morenzoni ¹, Robert E. Morey ³, Karl Mutch ¹, Helena Perazich ¹, Kimberly Perry ¹, Brock A. Peters ¹, Joe Peterson ¹, Charit L. Pethiyagoda ¹, Kaliprasad Pothuraju ¹, Claudia Richter ¹, Abraham M. Rosenbaum ⁴, Shaunak Roy ¹, Jay Shafto ¹, Uladzislau Sharanhovich ¹, Karen W. Shannon ⁵, Conrad G. Sheppy ¹, Michel Sun ¹, Joseph V. Thakuria ⁴, Anne Tran ¹, Dylan Vu ¹, Alexander Wait Zaranek ⁴, Xiaodi Wu ⁶, Snezana Drmanac ¹, Arnold R. Oliphant ¹, William C. Banyai ¹, Bruce Martin ¹, Dennis G. Ballinger ^1*, George M. Church ⁴, Clifford A. Reid ¹

¹ Complete Genomics, Inc., 2071 Stierlin Court, Mountain View, CA 94043, USA.
² Complete Genomics, Inc., 2071 Stierlin Court, Mountain View, CA 94043, USA.; Present address: Ion Torrent Systems, San Francisco, CA, USA.
³ Complete Genomics, Inc., 2071 Stierlin Court, Mountain View, CA 94043, USA.; Present address: San Diego State University, San Diego, CA, USA.
⁴ Department of Genetics, Harvard Medical School, Cambridge, MA, USA.
⁵ Complete Genomics, Inc., 2071 Stierlin Court, Mountain View, CA 94043, USA.; Present address: Life Technologies, Carlsbad, CA, USA.
⁶ School of Medicine, Washington University, St. Louis, St. Louis, MO, USA.

^* To whom correspondence should be addressed.
Radoje Drmanac , E-mail: rdrmanac@completegenomics.com
Dennis G. Ballinger , E-mail: dballinger@completegenomics.com

Genome sequencing of large numbers of individuals promises to advance the understanding, treatment, and prevention of human diseases, among other applications. We describe a genome sequencing platform that achieves efficient imaging and low reagent consumption with combinatorial probe anchor ligation (cPAL) chemistry to independently assay each base from patterned nanoarrays of self-assembling DNA nanoballs (DNBs). We sequenced three human genomes with this platform, generating an average of 45- to 87-fold coverage per genome and identifying 3.2 to 4.5 million sequence variants per genome. Validation of one genome data set demonstrates a sequence accuracy of about 1 false variant per 100 kilobases. The high-accuracy, affordable cost of $4,400 for sequencing consumables and scalability of this platform enable complete human genome sequencing for the detection of rare variants in large-scale genetic studies.