X-ray holography for sequencing DNA

In this paper we discuss the potential for application of X-ray holographic imaging techniques to thesequencing of DNA. We formulate an approximate model for the scattering of partially coherent X-raysfrom an oriented DNA fiber and show the feasibility of reconstruction of heavy atom label positionsfrom the X-ray scattering data. A series of simulations has been done to demonstrate the requiredreconstruction algorithms. An X-ray experiment is currently in progress to demonstrate the real feasibilityof the technique.The potential of X-ray imaging techniques for the sequencing of DNA is attractive because of theirinherently parallel nature. Hundreds or thousands of base pairs could be sequenced in a single set of X-rayimages. The fundamental idea is to attach heavy atom labels to a selected base type on the DNA fragmentto be sequenced. A large number (> 1012) of identical fragments can be constructed as an oriented fiberand illuminated with partially coherent X-rays. The heavy label positions can then be determined from therecorded pattern of scattered X-rays. If this operation is repeated for each of the four bases, the sequencecan be reconstructed.The phase determination problem is solved by attaching to each DNA fragment a reference label in aknown position. The scattered field then forms a Fourier transform hologram of the averaged DNA fragment.Because of the high photoelectric absorption of DNA relative to its coherent scattering cross-section, a singlemolecule would be damaged before an image could be formed. We solve this problem by distributing thedamage over a large number of identical copies of the DNA fragment.In this paper we model a relatively simple experiment whose objective is to form a Fourier transformhologram of a labelled DNA fiber using 1.54 A X-rays. We will first describe the hologram formation processand then the method for reconstructing the label positions.