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BioNano Genomics Readies Nanochannel Array Platform for SV Analysis, Genome Assembly


This article has been updated to note a wider price for a high-end microarray scanner.

Following a series of corporate changes over the last year and a new round of financing last month, BioNano Genomics is about to start beta testing for its nanochannel-based single-molecule DNA mapping platform.

The San Diego-based company will initially market the instrument, called Irys, for structural variation analysis and de novo genome assembly, though other uses, for example epigenetic mapping or pathogen fingerprinting, are feasible.

Earlier this week, BioNano Genomics, in collaboration with researchers at the University of California, San Francisco, published a proof-of-concept study in Nature Biotechnology showing that the technology can generate haplotype-resolved sequence motif maps of a complex region of the human genome that can be used as scaffolds for the de novo assembly of sequencing data.

At the end of June, BioNano Genomics, which changed its name from BioNanomatrix last year and currently has about 45 employees, raised $10 million in a Series B-1 round. The company will use the new funding to support its product development, establish a commercial infrastructure, and drive introduction of the Irys system to the market, according to Todd Dickinson, the firm's vice president of product development and marketing.

Existing investors Battelle Ventures, Domain Associates, and Gund Investment participated in the financing, which follows a $23.3-million Series B round a year ago.

Besides its new name, the company underwent a number of other changes over the past year or so, including the appointment of a new CEO, Erik Holmlin; additions to its management and development teams; the opening of new headquarters in San Diego (IS 6/21/2011); and a renaming of its platform from NanoAnalyzer to Irys. At the end of May, the company closed its original site in Philadelphia, where Han Cao, the firm's chief scientific officer, founded the company in 2003.

Dickinson, who was a founding scientist of Illumina, told In Sequence that BioNano Genomics is in the process of recruiting several beta testing customers and has been "extremely pleased with the amount of interest" in its technology. The timing of the full commercial launch will depend on the results of the beta program, and the system specs and list price have not been determined yet, though the instrument will likely be priced "roughly equivalently to a high-end microarray scanner," he said.

High-end microarray scanners currently sell for approximately $100,000 to $300,000, depending on the manufacturer, according to industry experts.

Initial target customers are large and mid-sized genome centers. Applications include structural variation analysis, comparative genomics, genome assembly, and sequence finishing, and the technology can complement current next-gen sequencing platforms. "Despite impressive improvements in NGS methods, they are still fundamentally limited by read length," Dickinson said. "Our solution provides a unique data type that provides the critical order and context that is missing in sequencing data."

Researchers may also use the technology in novel ways. "At the most basic level, our system allows a researcher to study very long-range genomic information at the single molecule level: this capability opens the door to a broad range of potential applications," he said.

At the heart of the technology lies a nanofludic chip with three sets of about 4,000 nanochannels, each channel with a diameter of 45 nanometers and a length of 0.4 millimeters. DNA molecules up to several hundred kilobases in length that have been fluorescently labeled at defined sites using sequence-specific nicking enzymes are drawn into the nanochannels via a voltage, held in their position, and imaged automatically. After that, the molecules are allowed to leave the channels and the process is repeated until the DNA is used up or the nanochannels become clogged.

Because the DNA molecules cannot fold back onto themselves inside the channels, they are kept in an elongated state, allowing researchers to measure their length and the distance between labels precisely. Sequence motif maps can then be constructed from the data.

BioNano Genomics' Irys system will likely compete with OpGen's Argus Whole Genome Mapping platform, which is also being marketed for structural variation detection and de novo assembly of large genomes (IS 10/18/2011).

But compared to optical mapping, which generates restriction maps of immobilized single DNA molecules, BioNano's nanochannel technology offers higher data quality and greater scalability, Dickinson claimed.

Other platforms also offer long-range mapping information. Pacific BioSciences, for example, has been touting the ability of its long sequence reads to improve the de novo assembly of short read data (IS 1/24/2012), and Complete Genomics just published a paper detailing its long fragment read technology, which provides haplotyping information (see other story, this issue).

However, "we don’t consider ourselves directly competitive with these technologies," which are sequencing-based, Dickinson said.

To test the capabilities of the Irys system, BioNano Genomics is currently collaborating with a number of external partners, including Pui-Yan Kwok's group at the Institute for Human Genetics at UCSF.

Mapping the MHC

In this week's Nature Biotechnology publication, Kwok's and BioNano's team employed the system to map the human major histocompatibility complex, MHC, a highly complex regions of the human genome that covers about 4.7 megabases of sequence, using BAC clones. While Kwok's lab has a prototype version of the instrument in house, the company generated the data for this study.

Using the Irys system, the researchers constructed sequence motif maps for 95 bacterial artificial chromosome clones covering the MHC region. The BAC clones, from two individuals, came from two libraries that were previously analyzed using Sanger sequencing by the MHC Haplotype Consortium, a collaboration between the Wellcome Trust Sanger Institute and the University of Cambridge.

Sequence motif maps from a mix of the two BAC libraries allowed the researchers to resolve the two haplotypes across the MHC region. They also sequenced the two libraries on an Illumina HiSeq 2000 and assembled the data de novo. They then placed the contigs onto the genome mapping scaffold and estimated the gap sizes between the contigs.

Comparing their sequence motif maps and contigs to the reference sequences reported by the MHC Haplotype Consortium, they found a number of discrepancies, which they said resulted from errors in the consortium's assembly.

Constructing the maps is relatively quick. According to Kwok, labeling the DNA takes about a day, and each image set takes about a half hour to capture. Sizing the DNA fragments and the gaps between the labels is automated, he said, but generating the maps takes several days and includes some manual quality control steps. "We get the raw data out really quickly, and then the downstream analysis takes a little bit more time," he said.

Compared to other genome mapping approaches, BioNano Genomics' method offers several advantages, according to Kwok. "This is really, really fast and it's also quite a bit simpler than all the other methods available," he said.

Because the DNA is kept in solution and flows continuously through the channels, the capacity of the platform is higher and the method is more flexible than others that immobilize the DNA, like optical mapping, he said. In addition, it is possible to tag the same DNA fragment with multiple labels, each specific for a certain sequence motif.

Kwok believes that the sequence motif maps could eventually replace array comparative genomic hybridization for structural variation analysis. While array CGH provides information about copy number variants, it cannot say where exactly they are located, which this method can. "That's going to be really important and useful for cancer genome analysis," he said.

The method could also be used to look for specific structural variations, for example translocation hotspots, he added.

Pathogen fingerprinting is another possible application. "For small organisms, especially pathogens, this would be a really easy way to go," he said.

But some experts believe that generating sequence motif maps from BACs is not sufficient to demonstrate utility for the technology. "What they have done you could do with a gel box," said David Schwartz, a professor of chemistry at the University of Wisconsin-Madison, who invented optical mapping. "The real test is, can you work with genomic DNA, can you work with shotgun DNA? And this paper does not show that."

Mapping BACs, he said, is a "recapitulation of work published elsewhere and doesn't meet modern standards for genome analysis. You have to work with genomic DNA in a tube as your library."

Kwok and his colleagues do acknowledge that the method could be improved, for example by increasing the DNA fragment size that can be routinely analyzed. The company has already pushed that size to one to two megabases, Kwok said.

The occupancy of the nanochannels could also be increased. Right now, not every channel is loaded with DNA, and there are gaps between the DNA molecules in a channel. "There is still a lot of empty space that we should be able to fill," Kwok said, which would increase the throughput.

Another improvement to the method would be allele-specific labeling, which is possible using padlock probes but not efficient enough yet, he said.

Epigenetic information could also be incorporated into the map, according to Ming Xiao, a former BioNano Genomics researcher who now works at Drexel University in Philadelphia. This could be achieved by labeling not only sequence motifs but also methylation sites.

Finally, the resolution of the map could be further increased. "The whole idea is trying to increase the information content," said Xiao. In collaboration with researchers at the University of Illinois at Urbana-Champaign, he and Kwok recently developed a DNA nicking site mapping technique and achieved a resolution of 100 base pairs, work that was recently published in Nano Letters.

But according to Schwartz, BioNano Genomics' competition is likely going to be formidable. "There are a lot of people who have woken up to working with very large genomic DNA," he said.

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