X-ray holography for sequencing DNA

In this paper we discuss the potential for application of x-ray holographic imaging techniques to the sequencing of DNA. We formulate an approximate model for the scattering of partially coherent x-rays from an oriented DNA fiber and show the feasibility of reconstruction of heavy atom label positions from the x-ray scattering data. A series of simulations has been done to demonstrate the required reconstruction algorithms. An x-ray experiment is currently in progress to demonstrate the real feasibility of the technique. The potential of x-ray imaging techniques for the sequencing of DNA is attractive because of their inherently parallel nature. Hundreds or thousands of base pairs could be sequenced in a single set of x-ray images. The fundamental idea is to attach heavy atom labels to a selected base type on the DNA fragment to be sequenced. A large number (> 1012) of identical fragments can be constructed as an oriented fiber and illuminated with partially coherent x-rays. The heavy label positions can then be determined from the recorded pattern of scattered x-rays. If this operation is repeated for each of the four bases, the sequence can be reconstructed. The phase determination problem is solved by attaching to each DNA fragment a reference label in a known 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 single molecule would be damaged before an image could be formed. We solve this problem by distributing the damage 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 transform hologram of a labelled DNA fiber using 1 .54 A x-rays. We will first describe the hologram formation process and then the method for reconstructing the label positions.