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Consortia Plan to Use Next-Gen Sequencing To Analyze Loci Found in Whole Genome Scans

Next-generation sequencing technologies will likely play an important role in large-scale sequencing studies that use results from whole-genome association studies as a starting point to pinpoint genetic variations linked to disease, according to several researchers involved in such studies.
Last week, three research consortia published genome-wide association studies in which they reported several new genomic regions and confirmed known ones that are linked to an increased risk of type 2 diabetes.
All three groups, which shared their data to reach their conclusions, are now planning sequencing projects to follow up on their results, In Sequence has learned.
The research teams worked with samples from the Wellcome Trust Case Control Consortium, the Finland-United States Investigation of NIDDM Genetics, and the Diabetes Genetics Initiative. They published their results online in three separate articles in Science last week.
Two of them used Affymetrix’s GeneChip Human Mapping 500K array set, while the third group used Illumina’s Infinium II HumanHap 300 BeadChips for their whole-genome genotyping analyses of several thousand samples in total.
The next step will be “to now sequence these loci exhaustively in patient cohorts” to pinpoint what genetic variations correlate with a phenotype, said David Altshuler, director of the medical and population genetics program at the Broad Institute and a leader of one of the studies. “And that, with traditional sequencing technology, would be extremely expensive, so there is a great interest in using these new technologies for that application.”
His team at the Broad is currently evaluating different new technologies, including 454’s and Illumina’s, for sequencing loci that have come out of whole-genome association studies and other genome analyses.
What is still missing, he said, is a method to select several hundred kilobases of DNA from the genome — the size of a locus of interest that may show variation in areas other than exons — for sequencing.
“Right now, we either can do whole-genome sequencing, which is still impractical at the level of thousands of people, or you can do PCR of a kilobase or two kilobases,” said Altshuler, who is also a professor at Harvard Medical School. But it is currently not possible to select larger stretches, he said. George Church and other researchers are working on methods to do this, he added.

The researchers now plan to sequence loci identified in whole-genome association studies “exhaustively in patient cohorts,” which would be “extremely expensive” with traditional sequencing technology. “So there is a great interest in using these new technologies for that application.”

Mark McCarthy, who led one of the other two studies, told In Sequence in an e-mail message last week that his team has already started a resequencing project using conventional sequencing provided by the Wellcome Trust Sanger Institute, but hopes to transition to Illumina’s sequencing technology “in the next few months,” which “seems the most likely [technology] to satisfy our resequencing needs.”
“We are certainly keen to move to the newer technologies (for reasons of cost and throughput) as and when the protocols for targeted regional resequencing are refined and robust,” said McCarthy, who is a professor at the Oxford Centre for Diabetes, Endocrinology, and Metabolism at the University of Oxford. “This looks like it will be possible in the not-too-distant future, given recent proof-of-principle data, but it’s certainly not the case that these protocols are yet ‘routine’.”
His team is continuing to collaborate with the other two research consortia beyond the initial phase of loci discovery, he said. “Given that we have found the same regions of interest, it makes sense to avoid redundant effort in the resequencing and fine-mapping thereof.”
His group, which has “good links” with the former Solexa group in the UK, is collaborating with the Broad Institute to “develop and implement approaches for the targeted resequencing of genomic regions of interest using the Solexa approach.” 

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