Climbing DNA's Ladder Rung by Rung

As soon as the near completion of the human genome was announced, commentators played up the payoff of finding genes for all sorts of diseases. But both almost-sequenced genomes are composites of several people. It's still an arduous task to figure out how a given person's genes differ from this standard. Now a new tool may provide researchers with a better way to pinpoint possible disease genes on a given chromosome--by reading DNA letter-by-letter.

For gene hunters, it's relatively straightforward to determine where a version of a particular gene lies on a given chromosome. But people carry two copies of each chromosome in every cell, one from mom and one from dad, and at particular sites in a gene the spelling in the DNA can differ. The process of figuring out which of these genetic differences lie on each chromosome is called haplotyping, and it's an important step toward identifying which version of a gene may cause disease. Right now, researchers must haplotype by analyzing genetic material from large families, or in their absence track gene frequencies in lots of individuals, a statistical process that is "prone to error," says geneticist Andrew Collins of Southampton University in the United Kingdom.

Looking for a hands-on alternative, a team led by Harvard chemist Charles Lieber and Massachusetts Institute of Technology (MIT) geneticist David Housman modified a popular microscope that uses an ultrasharp tip to map tiny surfaces. They capped the conventional microscope tip with a carbon nanotube--an ultra-thin cylinder of carbon atoms a mere nanometer or so across. The researchers tag unusual spellings of a particular gene with short strands of marker DNA linked to a reporter molecule that readily shows up in the microscope. Then they march the microscope tip down the atomic hills and valleys of a chromosome, and when it hits the reporter, the researchers know they've come to a given genetic variant, they report in the July issue of Nature Biotechnology.

The process is slow, but geneticists may be able to create arrays of hundreds of such ultrasensitive tips working in parallel to carry out ultrafast haplotyping, Lieber says. If such efforts succeed, says Robert Waterston, a geneticist who heads the genome sequencing center at Washington University in St. Louis, Missouri, the technique "could be the start of something impressive."

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