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Jun 15, 2010 (Vol. 30, No. 12)

Next-Generation Sequencing Moves to Next-Next Level

As Technology Proves Its Mettle and Advances Expand Usage, Applications Are Proliferating

  • Click Image To Enlarge +
    DNA and ions exit a carbon nanotube that can act as a combined nanopore and electrode for DNA sequencing. [Hao Liu/ASU]

    The emergence of next-generation sequencing marked a historical moment for biomedical and social sciences, one that promised to settle long-standing questions and, concomitantly, opened a new set of challenges. Sequencing of the human genome revealed that unrelated individuals are more similar to each other than previously thought. At the same time, the large number of single nucleotide polymorphisms and copy number variants that were unveiled, opened the need to sequence individual genomes more reliably and in a more time-efficient and cost-effective manner.

    Recent genetic and genomic advances revealed that mutations in one of several individual genes are often linked to the same condition or group of conditions, and new associations are constantly being unveiled.

    At Select Biosciences’ “Genomics Automation Congress” held recently in Boston, Birgit Funke, Ph.D., instructor of pathology at Harvard Medical School and associate director at the laboratory for molecular medicine at the Partners HealthCare Center for Personalized Genetic Medicine, talked about testing for mutations associated with cardiomyopathies and using next-generation sequencing to implement new tests that would examine many of the genes known to harbor disease-associated changes.

    Several classes of cardiomyopathies exist, and there are currently between 30 and 50 genes that have been individually linked to this group of conditions. “Testing for each of these genes using traditional Sanger sequencing technology is starting to be difficult to do in a cost-effective manner,” explained Dr. Funke.

    The laboratory for molecular medicine already expanded the number of tested cardiomyopathy genes by implementing a novel sequencing platform in 2007. Testing for all genes by next-generation sequencing represents the next goal that is already known to be technically feasible and, if introduced in the clinic, would offer great diagnostic benefits.

  • Epigenetics

    In addition to being a powerful tool to provide a vast amount of quantitative information about the genome, next-generation sequencing promises to re-shape the study of epigenetic modifications. “There is no doubt that next-generation sequencing is going to change epigenetic research measurements, and I suspect that in the next few years, everybody will be using next-generation platforms to explore DNA methylation and histone acetylation and modification,” said Jean-Pierre Issa, M.D., professor in the department of leukemia at the University of Texas MD Anderson Cancer Center and co-director of the center for epigenetics.

    Dr. Issa’s group uses next-generation sequencing to study DNA methylation and histone-modification changes that occur during aging or in response to therapeutic agents used in cancer treatment. “Next-generation sequencing provides an accurate, deep, and quantitative approach to study aging, and enables us to survey the genome to find the exact regions and genes that are affected and obtain information that was never available before.”

    Recently, Dr. Issa and collaborators reported that DNA methylation can be used to predict progression-free survival in patients with myelodysplastic syndrome.

    High-throughput DNA sequencing approaches promise to help the diagnosis and guide treatment decisions in many diseases and in many patients, and the combined analysis of the cancer genome and the epigenome promises to become a powerful diagnostic and therapeutic tool. “It is clear that the best way to study histone modifications across the genome is by next-generation sequencing. In terms of biology, this has been a revolution that transformed the field the same way as PCR did.”

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