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PubMed2000

Sequencing-by-hybridization at the information-theory bound: an optimal algorithm.

In a recent paper (Preparata et aL, 1999) we introduced a novel probing scheme for DNA sequencing by hybridization (SBH). The new gapped-probe scheme combines natural and universal bases in a well-defined periodic pattern. It has been shown (Preparata et al, 1999) that the performance of the gapped-probe scheme (in terms of the length of a sequence that can be uniquely reconstructed using a given size library of probes) is significantly better than the standard scheme based on oligomer probes. In this paper we present and analyze a new, more powerful, sequencing algorithm for the gapped-probe scheme. We prove that the new algorithm exploits the full potential of the SBH technology with high-confidence performance that comes within a small constant factor (about 2) of the information-theory bound. Moreover, this performance is achieved while maintaining running time linear in the target sequence length.

Algorithms↗

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Optimal reconstruction of a sequence from its probes.

An important combinatorial problem, motivated by DNA sequencing in molecular biology, is the reconstruction of a sequence over a small finite alphabet from the collection of its probes (the sequence spectrum), obtained by sliding a fixed sampling pattern over the sequence. Such construction is required for Sequencing-by-Hybridization (SBH), a novel DNA sequencing technique based on an array (SBH chip) of short nucleotide sequences (probes). Once the sequence spectrum is biochemically obtained, a combinatorial method is used to reconstruct the DNA sequence from its spectrum. Since technology limits the number of probes on the SBH chip, a challenging combinatorial question is the design of a smallest set of probes that can sequence an arbitrary DNA string of a given length. We present in this work a novel probe design, crucially based on the use of universal bases [bases that bind to any nucleotide (Loakes and Brown, 1994)] that drastically improves the performance of the SBH process and asymptotically approaches the information-theoretic bound up to a constant factor. Furthermore, the sequencing algorithm we propose is substantially simpler than the Eulerian path method used in previous solutions of this problem.

Algorithms↗