The.Algorithm.Design.Manual.Springer-Verlag.1998

War Story: Annealing Arrays
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War Story: Annealing Arrays
The war story of Section reported how we used advanced data structures to simulate a new method
for sequencing DNA. Our method, interactive sequencing by hybridization (SBH), involved building
arrays of specific oligonucleotides on demand. Although the simulation results were very promising to
us, most biologists we encountered were suspicious. They needed to see our technique proven in the lab
before they would take it seriously.
But we got lucky. A biochemist at Oxford University, got interested in our technique, and moreover he
had in his laboratory the equipment we needed to test it out. The Southern Array Maker [Sou96],
manufactured by Beckman Instruments, could prepare discrete oligonucleotide sequences in 64 parallel
rows across a polypropylene substrate. The device constructs arrays by appending single characters to
each cell along specific rows and columns of arrays. Figure shows how to construct an array of all
purine (A or G) 4-mers by building the prefixes along rows and the suffixes along columns. This
technology provided an ideal environment for testing the feasibility of interactive SBH in a laboratory,
because with proper programming it gave an inexpensive way to fabricate a wide variety of
oligonucleotide arrays on demand.
Figure: A prefix-suffix array of all purine 4-mers.
But we had to provide the proper programming. Fabricating complicated arrays requires solving a
difficult combinatorial problem. We were given as input a set S of n strings (representing
oligonucleotides) to fabricate an array (where m=64 on the Southern apparatus). We had to produce a
schedule of row and column commands to realize the set of strings S. We proved that the problem of
designing dense arrays was NP-complete, but that didn't really matter. My student Ricky Bradley and I
had to solve it anyway.
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