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Nano meets Bio technology and sees SNPs
By Bijal P. Trivedi

Scientists at Harvard and MIT are using nanotechnology to look directly at molecular-size variations between two copies of the same gene. Current technology allows biologists to determine the total contribution made by a pair of genes, but at present it is laborious to determine whether certain variations are associated together on one, or separately on both copies of the gene; these data are essential for correlating genetic variations with disease.

When samples of parental DNA are available, it is easier to match variations with either the maternal or paternal copy of the gene. In the absence of these DNA samples, the carbon probe described by Woolley et al. in the July issue of Nature Biotechnology may be particularly useful.

A carbon probe traces the topography of the DNA molecule with the attached molecular tags and generates a computer image.

The variations are first labeled with one bulky and one petite molecular tag and then observed using atomic force microscopy to see whether the tags bind to one or both copies of the gene.

A carbon nanotube, a rod about half the diameter of a DNA double helix, is used to "feel what the molecule looks like," and translates this into a computer image, says Charles Lieber, of Harvard University and an author on the report. The carbon rod is like a "high resolution phonograph needle" bouncing up and down very quickly as it travels over the surface of the DNA. When the carbon probe encounters a bulky molecular tag it is jolted over the tag and continues feeling the rest of the DNA. A smaller tag produces a smaller bump.

Computer images showing two different versions of the UGT1A7 gene, which has been implicated in cancer. One variation binds the large tag (left) while the other binds the small tag (right).

Genome researchers are devoting considerable resources to finding tiny variations in genes called single nucleotide polymorphisms, or SNPs, which they use to hunt down genes associated with diseases like cancer, hypertension, and diabetes. But just having a collection of SNPs alone will not help to find genes or to determine a person's risk unless the SNP's location is known.

(Left) When two variations are present in one copy of the gene, both the small and large tags bind, leaving the second copy free of tags. (Right) When both copies of the gene carry a single variation, each copy binds a single tag.

If a gene contains one SNP, only one tag will bind and the computer will show a thin line representing the DNA and a blob showing the location of the variation. Seeing the location of each SNP can allow scientists to determine whether a certain variation causes one or both copies of a gene to malfunction.

Lieber collaborated with MIT's David Housman to test whether the technique could distinguish between two samples of UGT1A7, a gene that inactivates carcinogens. In one sample the carbon sensor detected two variations within a single copy of the gene. In the other sample, each copy of the UGT1A7 gene had a single variation.

Lieber's long term goal is to fine-tune the carbon sensor to distinguish between the four chemical units that make up DNA and read the sequence directly from the molecule. Such fine resolution would eliminate the need for molecular tags because the letters making up the code could be read directly. A high throughput version of this technology could have broad applications in medical diagnostics, says Lieber.

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Woolley, A.T. et al. Direct haplotyping of kilobase-size DNA using carbon nanotube probes. Nat Biotechnol 18, 760-763 (July 2000).

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