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Apr 15, 2009 (Vol. 29, No. 8)

Novel Systems Zero In on the $100 Genome

Technology under Development Is Being Counted on to Provide Rapid and Affordable Sequencing

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    BioNanomatrix is applying semi- conducter nanofabrication technology to linearize long strands of DNA for massively parallel single-molecule genome analysis.

    Genome sequencing has gone through a precipitous drop in price since the first human genome was sequenced at a cost of billions of dollars. In fact, last year James Watson’s genome was sequenced for about $2 million. While this is still pricey, it represents a three orders of magnitude decrease on the way to the $1,000 price tag that would bring large-scale sequencing into the realm of feasibility.

    This price schedule still has a way to go to fulfill the dream of the $100 genome that would make personalized medicine available for all. At Cambridge Healthtech’s “Next Generation Sequencing” meeting held last month, companies presented their technologies designed to move the field ever closer to that goal.

    “Our company’s approach to sequencing is built on a three-tiered library strategy,” said Radoje Drmanac, Ph.D., CSO at Complete Genomics. The first consists of preparing DNA fragments of about 500 bp in length with 35 base paired-end reads, long enough to span the repetitive sequences. The second tier is composed of longer (5–10 kilo base pair) fragments with 35 base paired-end reads to cover most long repeats and rearrangements. Finally, the third tier consists of much longer fragments in the 100 kilo base pair size for much longer reads. 

    Dr. Drmanac described his company’s technology for obtaining independent sequence data from both homologues, in which the DNA from a small number (approximately 20) of human cells is divided between the wells of a 384-well plate. This means that the actual number of molecules diminishes to a handful per well. With such small numbers it is unlikely that any well will receive DNA from both homologous chromosomes.

    Another feature of the Complete Genomics platform is the use of amplified DNA clusters referred to as DNA nano-balls. This technology uses a small circular DNA template consisting of approximately 80 bases of genomic DNA and four synthetic adaptors producing a head-to-tail concatemer containing more than 200 copies formed into a ball. One mL of reaction volume generates over 10 billion DNA nanoballs, sufficient for sequencing an entire human genome. The amplification takes place in solution and avoids the cost and challenges of relying on single fluorophore measurements used by single-molecule sequencing systems, Dr. Drmanac explained.

    Unlike alternative approaches, clonal DNA amplification is not performed in emulsions or on surfaces. The amplification process occurs in solution and in a single reaction chamber, allowing for higher density and lower reagent usage. Additionally, the DNA-nanoball production process inherently produces clonal amplicons; it is not subject to the stochastic variation from limiting dilution.

    “Our platform can be scaled up to eventually accommodate millions of sequences per year at an affordable cost,” said Dr. Drmanac. The company’s present commercial plan starts in June with the sequencing of hundreds of genomes with the aim of moving this number into the millions in five to six years. “With this many analyzed genomes scientists and doctors will have in-depth insight in causes of the 1,000 most frequent genetic disorders.

    According to Dr. Drmanac, one of the major accomplishments has been the sequencing of a Caucasian HapMap sample generating 91x average read coverage (that is, a repetition of the sequencing 91 times to ensure maximum accuracy) of the genome using Complete Genomics third-generation genome sequencing technology. The sequencing revealed 3.3 million SNPs, 12% of them novel, and 40,000 insertions and deletions.

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