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Agilent to Provide Custom CNV Chips To Second Phase of WTCCC Study

Agilent Technologies said this week that it will provide custom whole-genome copy number variation-focused arrays to the Wellcome Trust Case Control Consortium, which will use them in the second phase of its 19,000-sample study to identify genetic variants influencing disease susceptibility in a variety of rare and common diseases.
Specifically, the consortium will attempt to link genes to tuberculosis, coronary heart disease, types 1 and 2 diabetes, rheumatoid arthritis, Crohn’s disease, bipolar disorder, autoimmune thyroid disease, ankylosing spondylitis, multiple sclerosis, breast cancer, and hypertension.
As part of its deal with the group, Agilent will design and fabricate the custom CNV chips, printing two arrays of 105,000 probes each per slide. Oxford Gene Technology, an Agilent certified service provider, will use Agilent’s Velocity 11 Bravo robot, acquired last December, to run the samples at OGT’s lab in Oxford, UK.
For Agilent, the high-volume deal will enable it to hone a CNV-focused microarray product line scheduled to launch later this year. It also gives the Santa Clara, Calif.-based company the opportunity to iron out the protocol for high-throughput, automated array processing.
“We expect that enhancements to the comparative genomic-hybridization workflow demonstrated in this project, such as the use of the Velocity 11 Bravo System and the use of a plate for purification will facilitate widespread use of Agilent CGH/CNV microarrays in high-throughput environments,” said Yvonne Linney, Agilent’s vice president and general manager of genomics.
“Independently of this project, Agilent also plans to provide a very high-resolution CNV-focused catalog array with 1 million features using data from public databases and Agilent’s own and collaborative CNV research,” she told BioArray News this week.
Matthew Hurles, a geneticist at the Wellcome Trust Sanger Centre in Hinxton, UK, said in a statement that the WTCCC “aims to characterize [the] most common structural modifications of DNA that may play a causative role in these diseases” and that the study requires “high-resolution microarrays with extremely reproducible performance.”
The first phase of the WTCCC began in 2005 and involved a collaboration of 24 leading human geneticists who analyzed more than 19,000 DNA samples from patients. The research was conducted at a number of institutes throughout the UK, including the Wellcome Trust Sanger Institute, the University of Cambridge, and the University of Oxford.
For the second phase, the WTCCC has inked deals with other array companies for SNP-genotyping projects. Last week, Affymetrix said that the WTCCC will use its SNP 6.0 Array to analyze 30,000 samples and 6,000 controls (see BAN 7/29/2008).

“Current CGH products do not specifically target CNVs, though they do provide coverage in CNV regions.”

The consortium is also using Illumina HD Infinium BeadChips for the project. Illumina said last month that 14 research groups involved in the WTCCC will analyze 90,000 samples for genetic links to 14 diseases and drug responses. These include schizophrenia, ulcerative colitis, psychosis, bacteriosis, preeclampsia, and statin response, and a genome-wide association study of learning difficulties (see BAN 7/1/2008).
Agilent’s contribution to the project differs in that WTCCC will use custom chips to look only at CNVs rather than SNPs and CNVs. Linney said that for a custom, CNV-focused microarray, researchers can select probes based on their own prior knowledge and expectation of where the important CNVs exist.
The WTCCC will “provide Agilent with information on their genomic regions of interest, whether annotated in the public databases or not, and Agilent will either select probes from their expanded CGH database or use their proven probe design pipeline to design new probes against the WTCCC regions of interest,” she said.
In recent years, surveying samples for copy number variation in genome-wide association studies has become increasingly popular. Both Affymetrix and Illumina make copy number variants available on their high-density SNP-genotyping arrays. Agilent has also looked to serve the demand for CNV-focused studies via its array CGH platform.
However, Linney said that there will be a few differences between the CGH arrays Agilent customers currently use to look at CNVs and the chips that will be provided to the WTCCC.
“The CGH product line is designed based on published sequences, whereas the WTCCC is not limited to this content when choosing their regions,” Linney said. She added that “current CGH products do not specifically target CNVs, though they do provide coverage in CNV regions.” Instead, current CGH products were designed to “provide coverage across the complete genome, with a focus on probes within genes.”
According to Linney, Agilent later this year plans to release new products that will specifically target CNVs.
Velocity 11 and OGT
While the standard protocol for labeling DNA and hybridizing it to the new CNV microarrays has not been significantly altered, modifications have been applied to the protocol to enable higher throughput, Linney said.
These modifications include using a plate-based method to clean the labeled DNA, and using Agilent’s Velocity 11 Bravo System liquid-handling system to process samples. The plate-based method, developed specifically for the WTCCC project, replaces a column-based clean-up method because it is “more amenable to the processing of large sample numbers,” Linney said. The new plate-based step will be described in a new CGH manual to be released later this year.
The Velocity 11 Bravo, meantime, will be used to automate most of the steps in the labeling process, from dispensing the DNA from its original plate into new plates, and through labeling. “This enables more efficient running of the samples with fewer lab technicians, and helps to minimize human errors and batch effects,” Linney said.
Agilent acquired Menlo Park, Calif.-based Velocity 11 for an undisclosed sum last year. Linney said that the Velocity robot has not been used in this capacity before, but that “Agilent and OGT have been taking many steps to optimize and validate” the new workflow.
“Agilent views this as an important project to help establish the Bravo as a tool for automating DNA labeling for Agilent CGH and CNV arrays,” she said, adding that the high-throughput workflow method will be made available to other Agilent customers via an application note later this year.
OGT, for its part, will process the WTCCC’s samples. The Oxford firm became a certified service provider in 2006, and Linney said that Agilent and OGT worked closely together earlier this year in a pilot project for the WTCCC to demonstrate the quality of Agilent data versus other suppliers’.
“Thanks to the results produced from the pilot study, the WTCCC selected Agilent as the platform provider, with OGT providing services,” Linney said.
OGT CEO Mike Evans told BioArray News this week that the firm considered a range of automation solutions, and chose the Velocity 11 instrument because it “combines very high-throughput automation with [a] high degree of precision even at low sample volumes.”
Velocity 11’s office in Melbourn, UK, also helped OGT to optimize its workflow. “They have a strong track record in drug screening, but this is a very different application,” Evans said. “They’ve given us a great deal of support in setting up the instrument for genomic applications.”
Like Agilent, OGT has used the deal with the WTCCC to expand its own offering. The company recently launched a high-throughput service, capable of scanning 1,000 samples per week for CGH, CNV, microRNA, and methylation studies. The service makes use of Agilent’s hybridization oven, scanner, and slide carousel, together with SciGene’s Little Dipper processor, the Velocity 11 Bravo, and a custom laboratory information management system.
“We’ve developed a protocol specifically for this study,” said Evans. “We are now marketing a high-throughput service and opening it up to people who have interesting large-scale projects,” he said. “It’s a full service offering for people that are really serious about outsourcing major projects.”

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