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NHGRI Awards $14.5M to Developers of '$1,000 Genome' Sequencing Techs


By Julia Karow

The National Human Genome Research Institute has awarded about $14.5 million in grants to nine research groups developing new DNA sequencing technologies to sequence a human genome for $1,000 or less.

Seven of the grants went to academic groups — one with ties to Oxford Nanopore Technologies — and two were awarded to companies, Stratos Genomics and Electron Optica.

The grants, which range in size from $500,000 to $3.6 million, last for two to four years. Three of the groups were previously funded through the program, while six are newcomers, though some of them have received other support from NHGRI.

The projects reflect a variety of approaches to DNA sequencing, ranging from observing changes in polymerase conformation to electron microscopy. Six of the projects involve nanopores or nanochannels, consistent with a shift towards these technologies in previous years — last year, for example, nanopore and nanogap projects accounted for more than half of NHGRI's funding commitments (IS 9/14/2011).

According to Jeff Schloss, NHGRI's program director for technology development, two trends are visible: "First, nanopore sequencing continues to make solid progress, and second, we haven't by any means come to the end of this community's imaginative search for novel solutions to the problem of rapid, low cost, high-quality genomic sequencing."

NHGRI estimates the current cost of sequencing a human genome to be less than $20,000 — half the amount it quoted a year ago. This includes labor, consumables, instrument amortization, informatics related to sequence production, library construction, data submission costs, and indirect costs. According to Schloss, the estimate is based on trends in NHGRI-funded projects and on claims from companies.

The new technologies to be developed under the program are supposed to bring this number down to $1,000. "We think our initial projection that the $1,000 genome can be achieved by 2014 is correct and expect that the cost will go lower than that, but we still see challenges in obtaining sequence of the quality that’s needed," Schloss said.

The total funding is in line with previous years — last year, for example, NHGRI awarded a total of $18 million under the program.

The following groups, listed by award size, were funded this year. Additional information about the grants can be found here.

Stuart Lindsay, Arizona State University
Instrument to optimize DNA sequencing by recognition tunneling
$4.1 million over 4 years
Collaborators: Jin He, Peiming Zhang, ASU, Predrag Krstic, Oak Ridge National Lab

Lindsay and colleagues have already shown that they can identify individual bases and read along a DNA molecule using so-called "recognition tunneling," where recognition molecules attached to electrodes transiently trap each base and provide distinct electronic signatures for all four bases and 5-methyl C. They now want to combine recognition tunneling with nanopore translocation using metal or graphene nanopores, and metal or carbon nanotube reading electrodes.

Mark Akeson, University of California, Santa Cruz
Optimization of processive enzymes for DNA sequencing using nanopores
$3.6 million over 3 years
Collaborators: David Deamer, UCSC; Jens Gundlach, University of Washington; Meni Wanunu, Northeastern University

Akeson and his collaborators plan to use DNA polymerase Phi29 to control the movement of DNA through a nanopore, including alpha hemolysin, MspA, and a solid nitride pore. They also want to use salt-tolerant DNA polymerases that allow for higher salt concentrations, which helps improve the sequence resolution. Oxford Nanopore Technologies has several exclusive licensing agreements with UCSC that cover Akeson's method for ratcheting DNA through a nanopore.

Jay Shendure, University of Washington
Massively parallel contiguity mapping
$1.8 million over 3 years

Shendure's group wants to use high-density, random, in vitro transposition to shatter genomic DNA in order to recover contiguity information at different scales. Specifically, they plan to develop a method for shattering genomic DNA with symmetric tags that inform the ordering of adjacent fragmentation events independent of the primary sequence content, a method for in vitro barcoding of fosmid or BAC-sized subsequences of a genome, and an in situ method for converting stretched DNA molecules into adaptor-flanked libraries, such that sequencing reads remain linearly ordered.

Marija Drndic, University of Pennsylvania
DNA sequencing using single-layer graphene nanoribbons with nanopores
$1.5 million over 3 years

These researchers plan to develop a DNA sensing technology that measures the current fluctuations of a graphene nanoribbon as single-stranded DNA passes through a pore in the ribbon. Specifically, they plan to fabricate thin GNR devices suitable for DNA sequencing, characterize their transverse electrical response to each of the four bases, and resolve DNA translocations by integrating off-the-shelf current amplifier technology.

Bharath Takulapalli, Arizona State University
High speed DNA sequencing by chemical recognition using novel nanopore technology
$916,000 over 3 years
Collaborators: Stuart Lindsay, Peter Wiktor

This group proposes a novel nanopore device concept to sequence DNA at very high translocation speeds. They suggest fabrication methods and exploratory studies for high-speed DNA information readout as well as device physical modeling and numerical simulations.

Mark Kokoris, Stratos Genomics
Sequencing by expansion
$829,000 over 2 years
Collaborator: Jens Gundlach, University of Washington

Stratos Genomics bets on the conversion of DNA into a synthetic molecule called "Xpandomer" prior to nanopore detection of the sequence. In this project, it wants to demonstrate the feasibility of this approach, using serial ligation of loop-modified tetramers that are highly specific to the DNA target.

Steven Soper, Louisiana State University A&M College
Polymer-based modular systems with nanosensors for DNA/RNA sequencing
$616,000 over 2 years

This group uses nanoscale sensors that identify individual DNA bases based on their characteristic flight time through a two-dimensional nanochannel that is fabricated in a thermoplastic, such as Plexiglas, via low-cost nanoimprint lithography and other replication-based techniques. The bases are released by a tethered exonuclease that feeds them into the nanochannel. The project will focus on developing a transduction modality that can measure the flight time of the nucleotides without a reporter molecule attached to them.

Wayne Barnes, Washington University in St. Louis
Fluorescent amino acid probe of template-strand bases
$608,000 over 2 years

This group proposes to decorate the inside of a DNA polymerase with one or more fluorescent reporter probes. As a single, fixed polymerase synthesizes DNA, it is expected to generate a reproducible flickering, and the flickering pattern might reveal the identity of each base. If the spatial position and angle of the base-touching fluor is different for each template base, the researchers also expect an alteration of the fluorescence of one or more FRET acceptor fluors positioned 10 to 15 angstroms away.

Marian Mankos, Electron Optica
DNA sequence imaging using a low energy electron microscope
$499,000 over 2 years

Electron Optica plans to develop a novel electron microscope to image the sequence of DNA with high accuracy. It will use a technique called monochromatic aberration-corrected dual-beam low energy electron microscopy, where two beams illuminate the sample with electrons, and the reflected electrons form a magnified image. The microscope has the potential to generate images of unlabeled DNA with nucleotide-specific contrast.

Have topics you'd like to see covered in In Sequence? Contact the editor at jkarow [at] genomeweb [.] com.

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