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Illumina-Genpathway ChIP-Seq Partnership Raises Questions About Future of ChIP-Chip: May 9, 2008 (rev. 1)

Genpathway, a San Diego-based chromatin immunoprecipitation, or ChIP, assays services firm, last week announced it will offer researchers whole-genome ChIP-sequencing services on Illumina’s next-generation sequencer, the Genome Analyzer.
The alliance will enable Genpathway to prepare its customers’ samples using its quantitative PCR-based FactorPath ChIP assays, and then to sequence those samples on the Genome Analyzer through Illumina’s sequencing services business. Genpathway will then analyze the data a final time before sending the results to its customers.
The deal, which is the first of its kind, also raises questions about the future of ChIP-based research on microarrays, leading some experts to predict that scientists will eventually abandon arrays for next-gen sequencing technology for this application.
According to Illumina and Genpathway, the service will enable researchers to identify and quantify transcription-factor binding sites across the entire genome. The companies plan to offer the services first for cell or tissue processing, antibody selection and qualification, and ChIP-DNA amplification.
Genpathway Chief Scientific Officer Mary Harper said in a statement that “one of the top applications for sequencing is ChIP” because ChIP assays are typically a “notoriously time-consuming and difficult procedure.” She said combining ChIP experiments with gene sequencing would provide researchers a “faster path to discovery.”
The company did not respond to a request for additional comment in time for this publication.
Genpathway first began offering quantitative PCR-based ChIP services in 2004. In August 2006 it inked a pact with Affymetrix to offer ChIP-on-chip services on Affy’s GeneChip tiling array system (see BAN 8/1/2006).
Though Genpathway’s decision to offer ChIP-seq will not affect its role as a certified Affymetrix service provider, and the firm will continue to offer array-based ChIP assays, the Illumina deal could portend a future migration of array users to next-gen sequencing technology for ChIP research, according to several experts.

“Now that sequencing has become so much faster and cheaper, the pendulum is swinging back.”

Bing Ren, the head of the Laboratory of Gene Regulation at the Ludwig Institute for Cancer Research, told BioArray News this week that he believes most researchers interested in ChIP experiments will eventually switch to ChIP-sequencing. Still, he cautioned that favorable array pricing would slow this migration by a few years.
“The long-term trend is that ChIP-seq is going to replace ChIP-chip, due to its high resolution and moderate cost,” he said. “However, in the short term, ChIP-chip is still the method of choice.”
Ren’s lab currently uses a method called genome-wide location analysis to study the in vivo function of transcription factors. GWLA combines the ChIP method with DNA microarrays to reveal the binding sites of DNA-binding proteins in living cells. In the past, Ren has also used NimbleGen array technology (see BAN 7/6/2005).
Trey Ideker, an assistant professor of bioengineering at the University of California, San Diego, also believes the conversion catalyst will be cost.
“Currently next-gen sequencing is expensive — at least three to five times more expensive than a typical microarray,” he told BioArray News this week. “If next-generation-sequencing can lower its cost a bit further to become more competitive with microarrays, there is no question it will become a disruptive technology.”
According to Ideker, he has seen such a switch occur before, but last time it was arrays that replaced sequencing. “In the mid ‘90s, cDNA/expressed-sequence-tag sequencing was the method of choice for measuring gene expression,” said Ideker. “Then, the microarray came along and displaced cDNA sequencing almost entirely for more than a decade. Now that sequencing has become so much faster and cheaper, the pendulum is swinging back.”
He added that “sequencing and microarray-based platforms have long been engaged in a head-to-head competition. This applies not just to ChIP but to gene expression and many other applications.”
Jason Lieb, an associate professor at the University of North Carolina, Chapel Hill, told BioArray News this week that though ChIP-seq will not replace ChIP-chip in the near term, the technology “will certainly replace ChIP-chip in many circumstances, for example when allele-specific information is sought.”
Lieb co-authored a paper in the March issue of Genome Research that compared ChIP-chip experiments across platforms and laboratories to narrow down the roots of disparities in ChIP-chip results between labs (see BAN 3/18/2008).
This week, he said that the main issues for researchers are cost and throughput. “At the moment, ChIP-seq costs more, the throughput is relatively low, there is much debate about how deeply a given sample needs to be sequenced, and the biases inherent in the method have not been carefully dissected,” he said. “Once all of these issues are addressed and the cost comes down, ChIP-seq will likely overtake arrays. But this will take some time.”
Kevin Struhl, a professor at Harvard Medical School and another co-author of the Genome Research paper, told BioArray News in March that a ChIP-seq comparison study of current next-gen sequencers, such as the Genome Analyzer and Applied Biosystems’ SOLiD System, would be the next logical step for the researchers involved in the ChIP-chip comparison project.
“ChIP-seq has not been subject to an analysis of this sort, and I think it would be very interesting to see how well it actually does,” said Struhl. “In ChIP-seq there’s still not even a paper that tells you what a false-positive or false-negative rate is.
“When you are doing high detail experiments that involve a lot of money, you should really do a test of the technologies, especially when there are not that many,” he said at the time.

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