Review abstract


Nature Biotechnology 27, 1013 - 1023 (2009)
Published online: 6 November 2009 | doi:10.1038/nbt.1585

The challenges of sequencing by synthesis

Carl W Fuller1, Lyle R Middendorf2, Steven A Benner3, George M Church4, Timothy Harris5, Xiaohua Huang6, Stevan B Jovanovich7, John R Nelson8, Jeffery A Schloss9, David C Schwartz10 & Dmitri V Vezenov11


DNA sequencing-by-synthesis (SBS) technology, using a polymerase or ligase enzyme as its core biochemistry, has already been incorporated in several second-generation DNA sequencing systems with significant performance. Notwithstanding the substantial success of these SBS platforms, challenges continue to limit the ability to reduce the cost of sequencing a human genome to $100,000 or less. Achieving dramatically reduced cost with enhanced throughput and quality will require the seamless integration of scientific and technological effort across disciplines within biochemistry, chemistry, physics and engineering. The challenges include sample preparation, surface chemistry, fluorescent labels, optimizing the enzyme-substrate system, optics, instrumentation, understanding tradeoffs of throughput versus accuracy, and read-length/phasing limitations. By framing these challenges in a manner accessible to a broad community of scientists and engineers, we hope to solicit input from the broader research community on means of accelerating the advancement of genome sequencing technology.

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  1. GE Healthcare Life Sciences, Piscataway, New Jersey, USA.
  2. LI-COR Biosciences, Lincoln, Nebraska, USA.
  3. Foundation for Applied Molecular Evolution, Alachua, Florida, USA.
  4. Harvard Medical School, Boston, Massachusetts, USA.
  5. Howard Hughes Medical Institute, Janelia Farm Research Campus, Ashburn, Virginia, USA.
  6. University of California, San Diego, La Jolla, Californi, USA.
  7. Microchip Biotechnologies Inc., Dublin, California, USA.
  8. General Electric Global Research Center, Niskayuna, New York, USA.
  9. National Human Genome Research Institute, NIH, Bethesda, Maryland, USA.
  10. University of Wisconsin-Madison, Madison, Wisconsin, USA.
  11. Lehigh University, Bethlehem, Pennsylvania, USA.

Correspondence to: Carl W Fuller1 e-mail: carl.fuller@alumni.upenn.edu.



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