Genome Technology Center

Enabling the $1,000 Genome

Jonas Korlach, Nanofluidics Inc, Menlo Park CA

We believe that biology has already built the optimal sequencing engine: the DNA polymerase. The enzyme can replicate DNA as fast as 1,000 bases per second, has a fidelity of sequence recognition that is often better than 99.999%, can provide a “read-length” of up to 100,000 bases, and consumes only tiny amounts of material in replicating an entire genome. To realize the full potential of this sequencing engine, we have developed technologies that allow us to observe individual nucleotide incorporation events in real-time at the single molecule level. Our sequencing-by-synthesis approach relies on two key technological innovations.  The first innovation is an optical nanostructure called the “Zero-mode Waveguide”. This structure allows to observe individual incorporation events in the presences of optimal concentrations of labeled nucleotides.  The second innovation is a method of labeling nucleotides that places the label on the leaving group of the nucleotide, so that upon incorporation the label is cleaved from the nascent DNA strand and diffuses away. This method ensures low background levels and prevents steric inhibition of the enzyme caused by the persistent presence of bulky fluorophore groups in the synthesized DNA. These two advances are combined to form a potential sequencing system that provides high speed, low reagent consumption, long reads, and multiplexing at a scale that will enable the de novo sequencing of a mammalian genome for less than $1,000.

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