Physical mapping by STS hybridization: algorithmic strategies and the challenge of software evaluation.

An important tool in the analysis of genomic sequences is the physical map. In this paper we examine the construction of physical maps from hybridization data between sequence tag sites (STS) probes and clones of genomic fragments. An algorithmic theory of the mapping process, a proposed performance evaluation procedure, and several new algorithmic strategies for mapping are given. A unifying theme for these developments is the idea of a "conservative extension." An algorithm, measure of algorithm quality, or description of physical map is a conservative extension if it is a generalization for data with errors of a corresponding concept in the error-free case. In our algorithmic theory we show that the nature of hybridization experiments imposes inherent limitations on the mapping information recorded in the experimental data. We prove that only certain types of mapping information can be reliably calculated by any algorithm. A test generator is then presented along with quantitative measures for determining how much of the possible information is being computed by a given algorithm. Weaknesses and strengths of these measures are discussed. Each of the new algorithms presented in this paper is based on combinatorial optimizations. Despite the fact that all the optimizations are NP-complete, we have developed algorithmic tools for the design of competitive approximation algorithms. We apply our performance evaluation program to our algorithms and obtain solid evidence that the algorithms are capable of retrieving high-level reliable mapping information.