An alternative to whole-genome sequencing

SHENZHEN, China—With a common interest in developing newapproaches to studying the Major Histocompatibility Complex (MHC) region—alarge cluster of genes that plays a critical role in the development orprogression of hundreds of diseases—Roche NimbleGen Inc. and BGI recentlyannounced they have developed technology that can be used to study this regionon genome-wide scale.

Found on the short arm of chromosome 6, MHC is a largecluster of genes that covers a 3.6Mb region including 150 expressing genes. MHChas been shown to play a critical role in many serious diseases such as cancer,AIDS, diabetes, arteriosclerosis and leukemia. Given its integral function inthe regulation of immune system, MHC has become a key target in drug researchand development for a number of diseases.

According to BGI, MHC shows a high degree of polymorphismthat complicates the studies of genes in this region, and its gene density (37per Mb) is five times higher than the average gene density of the whole genome(7 per Mb). Because of its polymorphic nature, linkage disequilibrium andinheritance of haplotype, MHC has been targeted for a wide range of researchapplications, including population evolution, paternity testing, HLA typing andorgan transplant matching.

The MHC region capture technology developed by Roche and BGIis an efficient strategy to study the whole MHC region by selectively enrichingthis region using an oligo hybridization approach, says BGI. The technology notonly targets the traditional MHC region (3.37MB), it also targets approximately1.6Mb of the regions surrounding MHC, providing a total of 4.97Mb (chr6: 28477797-33448354)and includes eight known haplotypes.

The technology is a faster and more cost-effective approachthan whole-genome sequencing, explains Jiang Hui, associate director of scienceand technology at BGI. Compared to existing genotyping technologies, the newtechnology enables targeted sequencing of 97 percent or more of the overall MHCregion, and close to 100-percent coverage of the gene coding regions, says Hui.

"The high accuracy of this new technology is demonstrated bya 99.42-percent concordance with traditional genotyping technologies," Huiadds. "But not only does this technology enable accurate genotyping of knownSNPs, it provides the opportunity to discover novel SNPs."

Discovering novel SNPs is important to furthering genotypingresearch because "those novel SNPs may exist with a very low, minor allelefrequency, or arise by novel mutation, and may be related with some rarediseases," says Hui. "By genotyping, we can only get the SNP information thatis already known because the genotyping array is designed according to thedbSNP or 1000 Genomes project."

In their partnership, China-based BGI was responsible forsequencing and developing the bioinformatic analysis pipeline, while Roche wasin charge of the probe design and capture reagents production.

"In autoimmunity diseases or other complex diseases that arerelated to the immune system, we could discover the disease-related genes byanalyzing large cohort of control versus case samples with this technology,"Hui says. "Investigating the function and signal pathway of those genes canhelp drug research."

Roche did not respond to requests for comment.