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Direct haplotyping of kilobase-size DNA using carbon nanotube probes


We have implemented a method for multiplexed detection of polymorphic sites and direct determination of haplotypes in 10-kilobase-size DNA fragments using single-walled carbon nanotube (SWNT) atomic force microscopy (AFM) probes. Labeled oligonucleotides are hybridized specifically to complementary target sequences in template DNA, and the positions of the tagged sequences are detected by direct SWNT tip imaging. We demonstrated this concept by detecting streptavidin and IRD800 labels at two different sequences in M13mp18. Our approach also permits haplotype determination from simple visual inspection of AFM images of individual DNA molecules, which we have done on UGT1A7, a gene under study as a cancer risk factor. The haplotypes of individuals heterozygous at two critical loci, which together influence cancer risk, can be easily and directly distinguished from AFM images. The application of this technique to haplotyping in population-based genetic disease studies and other genomic screening problems is discussed.

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Figure 1: Schematic illustration of the method for labeling specific DNA sites and detection with SWNT AFM probes.
Figure 2: Detection of labeled DNA sites with nanotube tips.
Figure 3: Direct haplotyping of UGT1A7 using SWNT probes.


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C.M.L. acknowledges support of this work from AFOSR. A.T.W. and C.G. acknowledge fellowship support from the Cancer Research Fund of the Damon Runyon-Walter Winchell Foundation and the Medical Research Council of Canada, respectively.

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Correspondence to David E. Housman or Charles M. Lieber.

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Woolley, A., Guillemette, C., Li Cheung, C. et al. Direct haplotyping of kilobase-size DNA using carbon nanotube probes. Nat Biotechnol 18, 760–763 (2000).

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