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Jan 1, 2009 (Vol. 29, No. 1)

Linking Disease to Gene Variations

Predisposition Based on Genomics Is Slowly Being Ascertained

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    Each human chromosome has dozens to hundreds of millions of base pairs of DNA, and variants in those base pairs can be associated with disease.

    New technologies and strategies for genetic testing and genomic analysis were the focus of several presentations at the recent American Society of Human Genetics (ASHG) meeting in Philadelphia. Understanding the molecular basis of disease, discerning inheritance patterns of genetic disorders, and clarifying the implications of predisposing genetic factors are core goals of genome-wide association studies (GWAS).

    As researchers and clinicians continue to unravel the mysteries of the human genome, they are looking to technology companies to provide next-generation sequencing and genome analysis tools to accelerate whole-genome and targeted DNA sequencing, SNP genotyping, and copy-number variation (CNV) analysis.

    Aravinda Chakravarti, Ph.D., ASHG president and professor at the McKusik-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, defined the challenges that must be overcome before the inevitable future of personalized medicine can become reality. “This reality cannot become routine or useful unless we can predict the phenotype of each of our unique genomes within which the vast majority of variation is rare and unique.

    “First, we need to understand the origin of variation. To gain an unbiased functional understanding we need to quantify the human mutation rate directly and how it is modulated. Second, progress in prediction will require not merely accumulating empirical facts but theoretical prediction of the functional content of any piece of DNA and the consequences of altering that sequence.”

    To achieve this, the field needs to be able to assess many more genomes, to integrate structural variation with mutation/SNP data, and to evaluate variation in noncoding regions of the genome. The hope is that next-generation sequencing technology will allow for sequencing of more genomes with greater coverage and for targeted resequencing to enable detection of rare disease-associated alleles such as small insertions, deletions, or inversions.

  • Medical Sequencing

    In a session entitled, “Using DNA Sequence to Detect Variation Related to Human Disease: The Promises and Challenges of Medical Sequencing,” Richard Wilson, Ph.D., professor at Washington University School of Medicine, explored new technologies for medical sequencing and mutation discovery in cancer. He described the disadvantages of traditional technologies: for example, array-based experiments only identify variation in exonic regions, and PCR-based resequencing is expensive.

    Dr. Wilson’s group has used Illumina’s next-generation sequencing platform to perform whole genome sequence analysis and to look for disease-linked variability in acute myeloid leukemia. The researchers identified eight validated somatic mutations, all of which were heterozygous, and two somatic insertions/deletions. The group is pursuing similar studies in glioblastoma.

    Stacey Gabriel, Ph.D., director of the Genetic Analysis Platform at the Broad Institute, gave conference attendees an overview of the ongoing 1000 Genomes Project and described how GWAS are being used as an unbiased discovery tool for identifying rare mutations that may have value as novel drug targets. Dr. Gabriel’s group developed a scalable process for exome sequencing that uses hybrid selection and capture of hybridized regions on beads to pull out the exonic regions of the genome.

    The 1000 Genomes Project will catalog all SNPs and CNVs with an allelic frequency >1% and make them available in a public database. The Project comprises three pilot programs: 4x genomic coverage of 180 people; 20x coverage of three case/parent trios; and 1,000 genes studied in 1,000 different people. One of the main challenges at present is how to integrate the disparate data derived from multiple different technology platforms and the development of hybrid platforms that can perform SNP and CNV genotyping on the same sample.

    Richard Gibbs, from Baylor College of Medicine, focused on directed sequencing approaches for exploring disease genomics and described his group’s work using Roche’s NimbleGen’s “rebalanced” arrays to capture targeted regions of the genome and Roche 454’s next-generation sequencing technology. The combination has allowed for greater than 94% coverage of the genome at 10x, according to Dr. Gibbs. He outlined the advantages of using high-density arrays of the exome instead of GWAS for medical sequencing studies: there is less data to manage; the experimental design has greater flexibility; the process is more readily scalable; it is easier to map variants; and the cost is substantially lower.

    Richard Lifton from Yale University, commented on the dramatic decrease in the cost of DNA sequencing over the past decade: from $100 per 1,000 high-quality bases in 1998 to less than $0.01 at present, using Illumina’s next-generation sequencing platform as an example.


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