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At ASHG, Affy, Illumina Tout New Exome Arrays as Complement for Sequencing and GWAS


By Justin Petrone

Longtime array rivals Affymetrix and Illumina last week introduced new chips targeting the exome, exonic variants in the protein-coding regions of the human genome.

Both firms believe that their respective exon arrays, scheduled to launch by the first quarter of 2012, will provide users with the ability to validate such variants in large sample numbers in a "fast and economical way."

In separate workshops at the combined International Congress of Human Genetics/American Society of Human Genetics meeting last week in Montreal, the two array vendors also sought to position their new offerings as both a way to follow up on variants discovered by exome sequencing in statistically powerful studies, as well as a complement to genome-wide association studies.

Citing an "explosion in content" generated by exome-sequencing initiatives, Candia Brown, Affy's director of strategic marketing for its DNA array portfolio, said during a presentation that the firm's customers are interested in using its forthcoming exome array to access a "significant proportion, 80 to 90 percent, of what we believe is the most functionally relevant" variation in the human genome.

"By focusing on exome sequencing and then applying that data to a GWAS context, it allows you to, in a very cost-effective way, do SNP discovery and then incorporate that into GWAS," said Brown.

Jennifer Stone, Illumina's DNA product manager, said that the San Diego firm plans to make its exome content available on several arrays, including its 250,000-marker, 12-sample Infinium HumanExome BeadChip, scheduled to launch in November; its 950,000, nine-sample OmniExpressExome BeadChip, also timed for a November release; and its 5-million-marker, four-sample HumanOmni5Exome BeadChip, expected to launch in 2012.

Stone said the latter chip, which will include 4.3 million markers from the firm's recently launched Omni5 BeadChip plus about 250,000 exonic variants, will interest those doing the "ultimate of array-based GWAS."

According to Stone, the exome content on the Omni5Exome will allow users to "dig deeper in the exome regions" than they would have been able to using other chips. "The aggregate will provide 4.5 million markers with an additional headspace for 250,000 markers for custom content," she said of the HumanOmni5Exome BeadChip. "You can really tailor this to be the ultimate array for a GWAS experiment."

Both offerings will be competitively priced. Brown said that Affy has been charging early-access customers $45 per sample during its early-access period, set to end on Dec. 30. An Illumina spokesperson said that the price for its 12-sample, InfiniumHumanExome BeadChip is $39 per sample. Its early-access period is also scheduled to conclude at the end of the quarter.

Mark McCarthy, a University of Oxford geneticist, said there is demand for such a product. "They have sold a huge amount of the arrays, maybe 400,000, and they aren't even on the market," McCarthy said of Illumina following the firm's workshop, citing in part the low early-access price. McCarthy noted that he contributed content to both vendors' arrays.

An Illumina spokesperson in an e-mail confirmed the chip's early-access price, but did not comment on how many InfiniumHumanExome arrays the firm had sold to date.

McCarthy said that the chips would be used in "some new association studies," and agreed that moving from sequencing studies to exome arrays could be attractive for those looking to validate their findings.

"We think it will work really well for people doing complex traits where we've done a lot of exome sequencing but we want to follow things up in large numbers in a cost-effective way," McCarthy told BioArray News. "And the exome chip will give us most of the stuff that we are interested in in a very accessible format."

Content 'Explosion'

According to Affy's Brown, the company's Axiom Exome Array will include roughly 300,000 functional variants, including "non-synonymous SNPs, 12,000 indels that have applications for loss of function, GWAS-compatible SNPs that we can apply to diverse cohorts," plus Y chromosome content, mitochondrial DNA, microRNA, and other variants. Customers will also have the ability to add an additional 50,000 SNPs selected from Affy's Axiom Genomic Database or other sequencing initiatives.

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Brown cited the "explosion of additional content" generated by the 1000 Genomes Project, as well as 16 exome sequencing initiatives that have been conducted in the past year that yielded some 600,000 new SNPs, as driving the need for such an array.

The market "has to have efficient and economical approaches to integrate that data and rapidly conduct GWAS," Brown said. "In addition to incorporating that content into our studies, we have to increase the sample size to ensure that we have sufficient statistical power," she said.

"By focusing on exome sequencing and then applying that data to a GWAS context," Affy's new chip allows users to in a "very cost-effective way do SNP discovery and then incorporate that into GWAS."

Affy's array will run on its GeneTitan instrument and customers will be able to process the array on plates containing 24, 32, 48, or 96 samples in parallel. The company is also in the process of validating the array on 1,200 samples from the 1000 Genomes collection at the National Human Genome Research Institute. "We will screen that array against very stringent quality-control metrics, and that data will be fully available in the beginning of 2012," she said.

Brown added that the exome content on the array could be included in other formats specified by the customer. "Not only can you add 50,000 SNPs to our off-the-shelf array, but you can also leverage the content and add it to a broader, higher-density array if you wanted to," she said. In total, there are 11 million markers to choose from in the firm's database, 8.8 million of which have been validated, she said.

'All Over the Map'

Illumina for its part has sought to make its exome content available in multiple catalog products. Stone said the rationale behind launching the Infinium HumanExome, the OmniExpressExome, and the HumanOmni5Exome BeadChips was that the company's customers are in various stages of conducting association studies, and therefore will need to access the exome offering in different formats.

"People are all over the map," Stone told BioArray News. "Some have already run GWAS on their samples, so they don't need to run a common variant analysis all over again," she said. "Budget considerations are also at play," she added. "We are trying to provide as much flexibility as we can for our partners through offering different designs."

Stone said during her presentation that the 250,000-marker InfiniumHumanExome is not intended to be a whole-genome genotyping array. "If we look at the coverage genome-wide that this provides, it is actually quite low," said Stone. "So we see this really as a supplement or an aggregate with a whole-genome approach."

The 12-sample InfiniumHumanExome BeadChip will begin shipping in November though the capability to add custom content to the chip will become available in the first quarter of next year. Stone estimated that Illumina customers could process more than 1,400 samples per week using the chip's automated workflow.

In terms of the OmniExpressExome and HumanOmni5Exome BeadChips, Stone said that Illumina sees a "nice synergy between the exon content as well as the whole-genome array."

Stone said the samples on the array "come from a number of different disease areas as well as normal samples from the 1000 Genomes Project," and come from a range of different populations, primarily European samples, but also a large component of African samples, as well as some Hispanic and Asian samples. "These are definitely biased towards putative functional variation and mostly observed in two or more studies," she noted.

In a statement last week, Illumina said its new BeadChip content was identified from "over 12,000 sequenced genomes representing diverse populations and a number of common conditions, including type 2 diabetes, cancer, and metabolic and psychiatric disorders."

The firm said it sees the array offering as a complement to next-gen sequencing projects. "Variants discovered through the power of next-generation sequencing have been deployed on Illumina BeadChips so that researchers can rapidly process large sample numbers to achieve greater statistical power in a cost-effective, straight-forward manner," Illumina said.

The company also disclosed another early-access customer in the statement, Benjamin Neale, assistant in medicine at Massachusetts General Hospital. "Prior to the consolidation of this exome content, we did not have a fast and economical array to survey almost all of the variation in the coding regions of the human genome," Neale said. "We can now study very rare coding variants in ... larger sample numbers than would be currently practical for sequencing."

Have topics you'd like to see covered in BioArray News? Contact the editor at jpetrone [at] genomeweb [.] com