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OpGen Combines Genome Maps, Sequencing for De Novo Assembly, Outbreak Analysis

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While OpGen's optical mapping technology is gaining traction for the assembly of genomes large and small, the company is also honing it for managing disease outbreaks and hospital-acquired infections.

So far, the Gaithersburg, Md.-based firm has placed about 40 of its Argus Whole Genome Mapping systems at customer sites, Richard Moore, OpGen's CSO, told In Sequence earlier this month. OpGen launched the system, which sells for approximately $200,000, in 2011.

Last year, it added Genome-Builder, a software module that combines sequence data with OpGen's maps to improve de novo assemblies of genomes up to 3 gigabases in size, both as a product for Argus customers and as part of its service. The firm is currently working on improving the cost and throughput of the Argus, he said, but is not yet ready to provide details.

While most of the privately held company's revenue currently comes from instrument and consumables sales, its service business is "growing rapidly," Moore said, for example from researchers who only need a single map for an organism they are working on. The company also plans to expand services for epidemiology, especially in hospitals, and is in the process of setting up a CLIA laboratory that will provide optical mapping, sequencing, and PCR assays.

Over the last year or so, OpGen has been busy validating its technology for different applications in demonstration projects, mainly through collaborations with academic and government research labs.

In the area of genome assembly, two research teams published large reference genomes at the end of last year that they assembled with the help of OpGen's whole-genome restriction maps.

One study, published by a group led by the Chinese Academy of Sciences and BGI-Shenzhen, sequenced the 2.7-gigabase genome of the domestic goat, using Illumina technology and maps produced by OpGen to join scaffolds into super-scaffolds (GenomeWeb Daily News 12/24/2012). The other study, led by Bejing Forestry University, BGI-Shenzhen, and the National Engineering Research Center for Floriculture in Beijing, assembled the 280-megabase genome of the Chinese plum, also by combining Illumina sequencing and optical maps that the researchers produced in house (GWDN 12/31/2012). Moore said that producing a genome map for a large genome costs on the order of thousands of dollars.

But the firm has also done work in human genomes. For example, last November at the American Society of Human Genetics meeting, OpGen presented whole-genome maps of human chromosomes from genomes previously characterized by FISH, array CGH, and next-gen sequencing and found that the maps were able to detect more than 95 percent of homozygous structural variations larger than 2 kilobases, including both balanced and unbalanced events. This suggests that optical maps are "an excellent complement to NGS for complete evaluation of human genomes" that "could eliminate the need for array CGH and FISH" to study the role of large structural variations, according to the conference abstract.

In collaboration with a large, undisclosed genome center in Europe, OpGen has also completed a whole genome map for a previously sequenced HapMap sample, work that the partners plan to publish in the near future. Comparing the map to other reference genomes, that study identified a number of sequence misassemblies, as well as several translocations, inversions, and indels, Moore said.

OpGen has also found that there is "still quite a bit of interest" in using genome maps to finish smaller genomes, he said. The company has been working with the Institute of Genome Sciences at the University of Maryland on automated assembly pipelines that use its genome maps to validate and improve small genomes.

The firm plans to roll out improved tools and pipelines that make finishing small genomes "much more automated and user friendly" to Argus customers in the near future, he added.

Last year, OpGen also said that it had partnered with the University of California, Davis, to improve microbial genomes for the US Food and Drug Administration-supported 100K Genome Project, which aims to sequence at least 100,000 infectious agents. UC Davis researchers plan to use OpGen's maps to help with genome assembly and validation. The UC Davis researchers are also working with Pacific Biosciences to finish genomes under the 100K project (IS 1/15/2013).

OpGen is also involved in several international large-scale microbial genome projects, for example the Global Microbial Identifier project, a collaboration between 200 scientists from about 30 countries, including the FDA, the World Health Organization, and the UK's Food Standards Agency and Health Protection Agency, that aims to develop a microbial genomic database "to address global public health and clinical challenges," according to its website.

While finishing small microbial genomes, in many cases, is "not nearly as complex" as completing large genomes, "there are still cases where having a map can really put things together," Moore said.

Besides applying maps to improve genome assemblies, OpGen is also working on applications in epidemiology, such as foodborne disease outbreaks, and, more recently, hospital-acquired infections. "Here, we're trying to figure out how to use both next-gen sequencing technologies and mapping to help with the workup of outbreaks," he said.

Whole-genome maps would be used first, followed by sequencing of interesting isolates or regions within them. Moore said that in a recently completed study, they found the maps were able to highlight specific genomic areas of interest, making it "a little bit easier to interpret what's going on, especially in the world of microbes where there are a lot of mobile elements, and you are kind of interested in what the genes in these mobile elements are."

In the US, OpGen is working with a consortium with the Centers for Disease Control and Prevention, the Association of Public Health Laboratories, and 13 state laboratories on public health projects, as well as with a group of European labs. These projects have been primarily focused on food and waterborne diseases and outbreaks, Moore said, but the company is now also starting to "push this into hospital-associated infections." It is in the early stages of collaborations with local healthcare facilities, he said, looking at combining mapping and sequencing to evaluate outbreaks as well as normal microbial contamination of hospitals and hospital workers.

Eventually, OpGen hopes these collaborations will translate into commercial activity. Moore said that public health labs in the US prefer to perform analyses in their own labs, "so we will be transferring Argus systems into representative labs in the US – I would hope that they would buy them – and then we would also transfer software and workflows for them to complete the map analysis and potentially integrate with sequence." While a number of public health laboratories in the US have their own next-gen sequencers, others outsource that work, he said. European labs, on the other hand, are generally more amenable to service work, so OpGen hopes to sell both instruments and services to them, he added.

For hospitals, in the long term, "we do believe there may be some interest in diagnostic information that comes out of this combination of mapping and sequence," Moore said, so OpGen is preparing to open a CLIA lab by the end of the third quarter of this year. Even though epidemiological service work will not require a CLIA facility, many hospitals would prefer it, and future diagnostic assays may require it, he said.

The CLIA lab will be outfitted with Argus mapping instrumentation as well as with sequencing equipment – OpGen currently has an Ion Torrent PGM – and PCR machines. Last year, the firm announced a partnership with Life Technologies to develop applications that use Ion Torrent sequencing and OpGen mapping for food outbreak and infectious disease analysis.

"We want to be able to do, as a service, complete workups of outbreaks," Moore said. To that end, the firm is also developing a variety of PCR assays to look at resistance and variant markers of organisms associated with hospital-acquired infections, he said.

In terms of competitors, Moore said that OpGen does run into Pacific Biosciences sometimes, which also offers longer-range structural variation analysis for microbes, but he said that OpGen is able to analyze longer variants, up to several hundred kilobases or even megabases in size.

Compared to BioNano Genomics, which also focuses on structural variation analysis, OpGen has a higher data throughput, he said, and does not require "fancy labeling," so it is easier to use.

Other potential competitors, such as Nabsys or Oxford Nanopore, do not have systems available yet, so "it is going to be a while until we can evaluate the performance," he said.

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