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The Complete Picture at Marco Island

Conference highlights include technology maturation from PacBio, Ion, and CGI.

By Kevin Davies

March 29, 2011
| MARCO ISLAND, FL—It is a testament to the remarkable progress in next-generation sequencing and analysis that when Harvard Medical School neurobiologist Tim Yu described the complete sequencing of 40 human genomes in a successful search for gene mutations that cause autism, it barely registered a ripple from the large audience.

Yu’s presentation was one of many standout presentations (see, “Sun Spots”) at this year’s Advances in Genome Biology and Technology conference.* While the conference lacked some of the technology razzamatazz of recent years, there were clear signs of the early maturation of newer technologies from companies such as Pacific Biosciences, Ion Torrent, and Complete Genomics (CGI), which supplied Yu with those 40 genome sequences.

Complete Genomics CEO, president and chairman Clifford Reid spoke exclusively to Bio•IT World about CGI’s recent accomplishments and near-term plans. Having taken the company public late last year, Reid was celebrating 1,000 sequenced human genomes and the public release of 60 completed and well-studied genomes. (The data are available from CGI’s website and mirrored on the Bionimbus Cloud.) One repeat customer, the Institute of Systems Biology in Seattle, recently placed an order for 615 genomes.

CGI is now sequencing up to 400 genomes per month, all to at least 40x coverage, and Reid expects to be “in the vicinity of 1,000 genomes per month” by the end of this year. CGI’s customer base remains firmly academic, but Reid says interest in big pharma is starting to grow. “Pharma tends to be more of a follower, with a few notable exceptions. We’re working with the exceptions,” he said, including “three flagship pharma accounts”—Genentech, Pfizer, and Lilly.

Cost and Quality

“We’re still the only company that’s published a 10-5 error-rate [human] genome,” Reid says. He asserts that Illumina’s current system consumes $5,000 in reagents, and that cost grows to $20-25,000 when the full cost of informatics and labor is included. By contrast, Reid says that CGI’s all-in cost for a complete human genome is under $10,000. “With all of it added in, we’re below $10,000 now. We’ve got a 2-3x cost advantage [over Illumina] and a 10x quality advantage.”

CGI currently charges $9,500 per genome for a minimum order of eight genomes. “You can’t pay $20,000 [per genome] any more, even if you try.”

The biggest competition to CGI’s service business appears to be BGI. “In the complete human genome space, they’re using Illumina technology, and we have distinct advantages for complete human genomes over that technology,” says Reid. “It’s more likely people would use BGI for one set of projects, and CGI for others.”

One of CGI’s original goals was to build a network of genome centers around the world. “From Mountain View, we can service North America and Western Europe quite effectively, though we might open a center in Europe to get closer to customers. But I think opening a center in Asia will get us access to customers that we really don’t have access to.”

Reid also indicated that CGI would consider expanding its suite of services, which until now has focused exclusively on complete human genomes. “We’re not going to do exomes,” he said, but says that transcriptomes are “squarely within our strategic footprint. We can and should be doing transcriptomes.”

The CGI team continues to drive advances in its proprietary DNA nanoball technology, increasing the density of the DNA on the slides. “Right now, the commercial systems are running slides with 3 billion spots at 700 nm center-to-center separation,” said Reid. “So the spots are separated by the wavelength of red light. We’re on our way to the wavelength of blue light!” Reid also said that plans are advanced to commercialize CGI’s newly patented long-fragment read (LFR) technology. (A paper describing the approach and applying it to a genome sample is about to be submitted.)

Among the advantages to the LFR approach is chromosome separation, which phases out the two parental sets of chromosomes. “It also has a wonderful property of error detection and correction,” says Reid. “There’s a whole category of errors it can detect—the number of errors it is catching is very high. Right now our genomes are 10-5. These LFR genomes will be 10-7—another factor of 100.

“From a clinical perspective, a 10-5 genome is 30,000 errors in the genome, which gives you pause. But a 10-7 genome is 300 randomly distributed errors in the genome. That’s virtually perfect! We think we’ll be doing clinical grade genomes by the end of the year.” CGI is currently in the early stages of preparing for CLIA certification.

CGI’s reported ability to sequence genomes to high accuracy and phasing and at less than $10,000 per sample would appear to put it in line for a shot at the Archon Genomics X PRIZE. But CGI’s Achilles’ heel is turnaround time; the X PRIZE calls for a turnaround time of ten days. “Our turnaround times are longer than that,” says Reid. “But in terms of price, phasing, quality, we’re well within the X Prize spec.”

Autism Genes

At AGBT, further validation of Complete’s genome service was provided in Yu’s presentation. Yu and colleagues have focused on families from the Middle East, collecting some 200 families with cases of autism, analyzing 40 sequenced genomes from CGI. On average, an individual genome contained some 10,000 potentially pathogenic variants when cross-referenced to the databases. Those are then filtered further to focus on novel variants that follow a consistent inheritance pattern in the affected families. Yu’s team documented mutations in known metabolic genes (PEX7, AMT) and other candidate genes that play roles in histone modification and axon guidance.

“There will be no ‘autism gene’ but many autism genes,” said Yu. •

*Advances in Genome Biology and Technology; Feb 2-5, 2011, Marco Island, FL.

This article also appeared in the March-April 2011 issue of Bio-IT World Magazine. Subscriptions are free for qualifying individuals. Apply today.
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