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Nov 1, 2010 (Vol. 30, No. 19)

Microarray Technology Moves to the Fore

Improved and Reconfigured Platforms Help Researchers Maximize Genomics Studies

  • CGH Tools

    Agilent Technologies offers a family of microarray products that can answer any nucleotide question you may wish to pose in comparative genomics or gene expression, according to Glenda Anderson, director of genomic diagnostics.

    The company has an online customization tool, known as eArray, through which customers can design microarrays from a database of probes or choose their own specific oligonuclotide sequences, thus enabling researchers to investigate diagnostic questions of import.

    A feature of eArray, known as the Probe Score, predicts the probes’ expected performance in a given hybridization setting. The capability has reportedly been put to use by a number of research consortia around the world, investigating genomic questions in developmental disorders, autism, IVF, and oncology.

    An example of how the eArray technology is applied comes from the ISCA consortium, a worldwide group of 130 laboratories investigating developmental disorders. Founded by David Ledbetter, Ph.D., the ISCA team developed a microarray design and a set of probes targeted to regions known to be involved in pediatric developmental delay.

    Anderson believes it is important to distinguish between DNA-based tests used to detect polymorphisms and copy-number changes as opposed to RNA-based measures of gene expression, since the former are inherently more reproducible. “The reliability of microarray comparative genomic hybridization data points a clear path to FDA clearance, whereas the issue is much more nuanced in the case of gene-expression data.” 

    Agilent has an active program of clinical discovery, Anderson says. “Many of our customers are clinical researchers with whom we are forging coalitions to drive discovery. We see our role as that of a catalyst, playing a supporting function to help bring together groups of clinical researchers so that they may share their data.

    “We just launched a CGH + SNP microarray product for looking at copy-number changes and simultaneously identifying regions where loss of heterozygosity has occurred. Detecting copy-neutral LOH is important to clinical researchers seeking to understand the DNA changes that influence developmental disorders and many cancers.”

    While advances in array technology hold great promise for the understanding gene function and the development of therapies derived from these findings, careful controls and monitoring are essential for success. “We view consumer-based microarray tests with caution because the interpretation of this complex data really belongs in the hands of board-certified professionals.”

  • Pursuing the Genome

    The NimbleGen array platform was designed to help researchers better understand the genome and the affect of genetics on disease, according to Xinmin Zhang, Ph.D., senior product manager at Roche NimbleGen.

    The NimbleGen Sequence Capture Exome technology is focused on the most biologically relevant part of the genome, the exome, capturing only the coding exons that are the most functionally relevant and the best understood 1% of the genome.

    The company recently introduced the SeqCap EZ Human Exome v2.0, which allows researchers to capture all RefSeq coding exons and miRNA genes in a single tube. It employs empirical rebalancing, a probe-optimization method, in order to enhance capture uniformity. This process is based on real capture and sequencing data derived from optimization of probe density and coverage for all regions.

    Because the platform reduces probe density on regions with high-capture efficiency while increasing it in regions with low-capture efficiency, it provides uniformity leading to detection of over 90% of variants in the exome with a single lane (~3 Gb) of sequencing.

    Other recent introductions for the cytogenetics research market include NimbleGen CGX cytogenetic arrays, according to Emily A. Rorem, director for product management. The CGX design is optimized for constitutional chromosome analysis to identify copy-number variation in the genome, which may be associated with recognized and unknown syndromes.

    The assay interrogates the entire genome and has a high resolution of coverage over targeted chromosomal regions, including over 200 recognized genetic syndromes, 675 functionally significant genes, and the subtelomeres and pericentromeric regions, she adds. The CGX array portfolio specifically addresses cytogenetic applications and provides scalability with three different array formats to process 3, 6, or 12 samples per slide, she adds.

    “In the future, we will expand the capabilities of our long oligonucleotide array platform to include SNP detection, providing accuracy and flexibility,” Dr. Zhang reports. “This technology will aid researchers in validation and follow up on SNPs detected through whole-genome or whole-exome sequencing.”

    The company also intends to achieve GMP compliance followed by subsequent submission for clearance of select array products for the cytogenetics market to the FDA, Rorem explains. The SNP program described by Dr. Zhang will also play an important role in the areas of oncology research.

    Dr. Zhang emphasizes that bringing new products through the approval process requires new content, which is not always readily available and requires significant research and advanced tools.

    “With the recent progress in genomic technologies, most notably in next-generation sequencing, many more genetic and epigenetic markers will be discovered and validated for diagnostic use. We expect that arrays will be an ideal platform to develop tests for this novel content and new markers.

    “For many genomic studies, researchers are discovery-driven and not necessarily hypothesis-driven. Therefore, the focus and end results of the research do not always establish the link between diseases and genes. This doesn’t necessarily reflect on the technology as long as arrays continue to deliver accurate and comprehensive data. The key bottleneck to this issue is in the experimental design and data analysis.”

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