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Genome Sequencing in Open Microfabricated High Density Picoliter Reactors

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 60×60 mm2 fibreoptic slide containing 1,600,000 individual wells and is able to sequence 25 million bases, at 99% or better accuracy (phred 20), in a 4 hour run. To provide sequencing templates, we clonally amplify DNA fragments on beads in the droplets of an emulsion. The template-carrying beads are loaded into the wells to convert each into a picoliter-scale sequencing reactor. We perform sequencing by synthesis using a pyrosequencing protocol optimized for solid support and the small dimension of the open reactors. Here we show the utility, throughput, accuracy and robustness of this system by shotgun sequencing and de novo assembling the Mycoplasma genitalium genome with 96% coverage at 99.96 % accuracy in one run of the machine. DNA sequencing has dramatically changed the nature of biomedical research and medicine. Reductions in the cost, complexity and time required to sequence large amount of DNA, including improvements in the ability to sequence bacterial and eukaryotic genomes will have significant scientific, economic and cultural impact. Large scale sequencing projects, including whole genome sequencing, have usually required the cloning of DNA fragments into bacterial vectors, amplification and purification of individual templates, followed by Sanger sequencing 1 using fluorescent chain-terminating nucleotide analogues 2 and either slab gel or capillary electrophoresis. Current estimates put the cost of sequencing a human genome between $10 Correspondence and requests for materials should be addressed to J. M. Rothberg (jrothberg@454.com). Sequences for M. genitalium and S. pneumoniae were deposited at DDBJ/EMBL/GenBank under accession numbers AAGX01000000 and AAGY01000000 respectively.. *These authors contributed equally to the work. Supplementary Information accompanies the paper on www.nature.com/nature. NIH Public Access