Highly parallel genomic assays

A review of Highly parallel genomic assays

Recent developments in highly parallel genome-wide assays are transforming the study of human health and disease. High-resolution whole-genome association studies of complex diseases are finally being undertaken after much hypothesizing about their merit for finding disease loci. The availability of inexpensive high-density SNP-genotyping arrays has made this feasible. Cancer biology will also be transformed by high-resolution genomic and epigenomic analysis. In the future, most cancers might be staged by high-resolution molecular profiling rather than by gross cytological analysis. Here, we describe the key developments that enable highly parallel genomic assays.

Summary:

  • Highly parallel genomic assays have two fundamental characteristics: a highly parallel array-based read-out and an intrinsically scalable, multiplexing sample preparation.
  • The power of highly parallel genomic assays is that they tend to follow the principle behind Moore’s law: the amount of information extracted from a sample increases linearly with the number of probes on the array, whereas the overall cost of the assay tends to increase at a much slower rate.
  • These general concepts are being applied successfully to an increasing variety of assays, including gene-expression profiling, SNP genotyping, genomic copy-number analysis, measurement of allele-specific expression levels, and methylation status.
  • Early genomic assays, such as gene-expression profiling, relied only on sequence-specific probe hybridization to confer specificity. The next generation of assays have made use of enzymatic discrimination in addition to hybridization to increase specificity and to enable assay designs that extract more information.
  • Data quality, reproducibility and robustness of intrinsically parallel assays that use enzymatic discrimination have been shown to be high, defying the conventional wisdom that increasing sample complexity automatically results in lower data quality.
  • The technology of highly parallel assays is enabling a revolution in genomics that has far-reaching implications for molecular biology and human health. Increasingly, ambitious projects that aim to be more comprehensive in their approach to genomic analysis, such as the International HapMap Project, the ENCODE Project, and the Cancer Genome Atlas, are reliant on new, highly parallel assay technologies.
  • The orders of magnitude decrease in cost and increased speed and accuracy that are provided by highly parallel assays have brought us to the dawn of a potentially revolutionary new era of discovery in human genetics that will be based on comprehensive, high-resolution genetic mapping.
  • Such studies might require about a billion or more genotypes, and were impractical prior to the advent of the assays that are described in this Review. A few years ago, the genotyping costs for such a study would have been in the hundreds of millions of dollars. Today, the costs would be a few million dollars, with far higher data quality and completeness, and genotyping can be carried out in a few weeks instead of many years.
  • Parallel assay systems are assisting a similar revolution in the field of DNA sequencing, and will probably enable powerful new comprehensive studies that are prohibitively costly today.
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