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Zymo Research Refines Focus on Epigenetic Sequencing Services

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Originally a DNA and RNA extraction and purification company, Zymo Research is now focusing on epigenetics. In the crowded space of sequencing services, it is emphasizing methylation and hydroxymethylation sequencing to set it apart from other providers.

The Irvine, Calif.-based company offers methylation and hydroxymethylation profiling, including targeted methylation sequencing and whole-genome bisulfite sequencing services, on Illumina sequencing platforms. It has three different offerings for genome-wide methylation sequencing — Methyl-MiniSeq, Methyl-MidiSeq, and Methyl-MaxiSeq, Marc Van Eden, the company's vice president of business development and marketing, told In Sequence.

The Mini workflow captures around 10 percent of the methylome, Midi around 30 percent, and Maxi covers the entire methylome.

The company uses a combination of bisulfite sequencing with its own proprietary library prep workflows, Van Eden said. The Mini and Midi workflows use a combination of restriction endonucleases to cleave at CG sites. "Those would be primarily in promoter regions and CpG islands, but also for certain exons, introns, and enhancer regions as well," he said.

The Mini workflow is based on reduced representation bisulfite sequencing and can detect 3 million to 4 million unique CpG sites, covering greater than 85 percent of all CpG islands and 80 percent of all gene promoters, while the Midi workflow expands on the Mini pipeline to cover 8 million to 9 million CpG sites, and includes some genetic regulatory elements, gene bodies, and repeated DNA sequences.

To analyze hydroxymethylation, the company offers reduced representation hydroxymethylation sequencing.

The company has an Illumina MiSeq, which it uses for the targeted sequencing applications. For customers who want whole-genome methylation or hydroxymethylation sequencing, it contracts out the sequencing component on the HiSeq to unnamed providers.

Van Eden did not elaborate on Zymo's proprietary methods, but said that the technology allows for steps to be consolidated so the sequencing can be done with very low sample input requirements. Typically, the company asks customers for a few hundred nanograms, but can go as low as 50 to 100 picograms, he said, which is important particularly when working with formalin-fixed paraffin-embedded tissue, or tissue extracted from needle biopsies.

Zymo also provides the bioinformatics analysis, delivering an "easy to digest report," Van Eden said. Additionally, it offers RNA-seq, mitochondrial sequencing, ChIP-seq, and DNA sequencing services. "If someone comes to us for these … epigenetic services, they may also want to add a layer of RNA-seq or maybe a sprinkle of genetic sequence data."

The firm's customers include researchers in the agricultural field, as well as more clinically focused customers like pharmaceutical companies.

"Clients include people in agricultural science studying the polar bear, soybean, duckbill platypus — all sorts of agricultural and important organisms," he said.
On the ag-bio side, customers want methylation profiles for a variety of reasons. For instance, said Van Eden, the earthworm is used as a test model for various toxicities in soil and "there can be a bounty of information in its methylome, where subtle changes are occurring in response to its environment," he said.

Additionally, in the case of crop sciences, researchers involved in crop improvement projects may want to analyze the methylation or hydroxymethylation profiles for certain crops to see whether there are epigenetic biomarkers related to the production of a certain protein, or to traits that confer drought tolerance.

Zymo's pharmaceutical and diagnostic customers are typically looking for epigenetic biomarkers that relate to disease prognosis. Zymo can do a broad genome-wide scan for such biomarkers, said Van Eden, but the company also has technology available to validate putative biomarkers. For instance, customers could do whole-genome methylation sequencing to "identify 200 biomarkers that are important for a certain disease, [and then] plug them into a validation system and settle on 10, 20, or 50 markers for further study," he said.

Van Eden said that because Zymo is seeing an increasing number of customers from the pharmaceutical and diagnostic market it is considering applying for CLIA certification for its laboratory, which is often desired when pharmaceutical companies are incorporating this type of analysis into their clinical trials, he said.

It terms of competition, there are a slew of companies that offer sequencing services, including methylation sequencing. Illumina itself offers sequencing services through its Illumina Genome Network, not to mention providers such as BGI, PerkinElmer, and GATC Biotech. However, Van Eden said that Zymo occupies its own niche by focusing on epigenetics, so it does not view these other service providers as competitors. It likely does compete with NXT-Dx, a Belgian firm founded two years ago that uses methylation sequencing technology developed at the University of Ghent (IS 9/11/2012).

Looking ahead, while Zymo currently uses only Illumina sequencing technology, Van Eden said that the company is always evaluating other sequencing platforms, and is keeping its eye on emerging technology like Oxford Nanopore. He said that Zymo has spoken with Pacific Biosciences about its platform, because of the system's unique ability to analyze epigenetic marks through machine's kinetics, but as of yet is not planning to purchase a PacBio system.

He said PacBio's input requirements are still too high and the platform is less cost-effective for deep sequencing than other systems. "For genome-wide coverage and at a particular locus to get the actual frequency of methylation, you need deep sequencing and a high amount of coverage," he said.

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