Editors' ChoiceHuman Genetics

Personalized Medicine Progresses One Base at a Time

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Science Translational Medicine  06 Jan 2010:
Vol. 2, Issue 13, pp. 13ec2
DOI: 10.1126/scitranslmed.3000769

In 2003, the sequencing of the human genome was greeted with much fanfare and attendant speculation on how this feat would inform disease biology and gene-environment interplay and pave the way for genomics-based personalized medicine. Clinical laboratories and companies such as 23andMe use DNA array, single-nucleotide polymorphism–based genotyping techniques to detect common, disease-related genetic variants in human genomes quickly and at a reasonable cost. However, personalized disease diagnosis, prognosis, treatment, and prevention can only be fully realized through the characterization of rare genetic variations identified by the complete sequencing of many individual human genomes—a process that is both time-consuming and expensive (material costs alone are $48,000 for a single genome). Now, on the brink of a new decade, Drmanac et al. describe in their recent Science paper a new genome-sequencing platform that addresses both the time and cost issues that plague current methods.

The authors repeatedly cut genomic DNA into fragments, inserted directional adaptor sequences, and used these templates to produce hundreds of tandem copies of the fragments. Palindromes in these sequencing substrates spurred self-assembly into coils of single-stranded DNA. These DNA "nanoballs" were then adhered to grid-patterned silicon surfaces with a high DNA-to-array ratio, and the DNA was sequenced by means of combinatorial probe-anchor ligation sequencing chemistry. This method reads 10 contiguous bases from the ends of the adaptor sequences and does so with high fidelity and low reagent consumption. The authors used their platform to sequence three human genomes with 45- to 87-fold coverage per genome. In this process, they pinpointed 3.2 million to 4.5 million sequence variants in each genome at an accuracy of ~1 false variant per 100 kilobases and a consumables price tag of $4400 per genome. In the spirit of New Year's predictions, the authors anticipate that this platform will drive the discovery of rare genetic variants in large genomic studies.

R. Drmanac et al., Human genome sequencing using unchained base reads on self-assembling DNA nanoarrays. Science 327, 78–82 (2009). [Full Text]

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