We present probabilistic arithmetic automata (PAAs), a general model to describe chains of operations whose operands depend on chance, along with two different algorithms to exactly calculate the distribution of the results obtained by such probabilistic calculations. PAAs provide a unifying framework to approach many problems arising in computational biology and elsewhere. Here, we present five different applications, namely (1) pattern matching statistics on random texts, including the computation of the distribution of occurrence counts, waiting time and clump size under HMM background models; (2) exact analysis of window-based pattern matching algorithms; (3) sensitivity of filtration seeds used to detect candidate sequence alignments; (4) length and mass statistics of peptide fragments resulting from enzymatic cleavage reactions; and (5) read length statistics of 454 sequencing reads. The diversity of these applications indicates the flexibility and unifying character of the presented framework. While the construction of a PAA depends on the particular application, we single out a frequently applicable construction method for pattern statistics: We introduce deterministic arithmetic automata (DAAs) to model deterministic calculations on sequences, and demonstrate how to construct a PAA from a given DAA and a finite-memory random text model. We show how to transform a finite automaton into a DAA and then into the corresponding PAA.
@cite_70: Motivation: Genomics and proteomics studies routinely depend on homology searches based on the strategy of finding short seed matches which are then extended. The exploding genomic data growth presents a dilemma for DNA homology search techniques: increasing seed size decreases sensitivity whereas decreasing seed size slows down computation. Results: We present a new homology search algorithm ‘PatternHunter’ that uses a novel seed model for increased sensitivity and new hit-processing techniques for significantly increased speed. At Blast levels of sensitivity, PatternHunter is able to find homologies between sequences as large as human chromosomes, in mere hours on a desktop. Availability: PatternHunter is available at http: www. bioinformaticssolutions.com, as a commercial package. It runs on all platforms that support Java. PatternHunter technology is being patented; commercial use requires a license from BSI, while non-commercial use will be free.
@cite_46: 
@cite_58: Optimal spaced seeds were introduced by the theoretical computer science community to bioinformatics to effectively increase homology search sensitivity. They are now serving thousands of homology search queries daily. While dozens of papers have been published on optimal spaced seeds since their invention, many fundamental questions still remain unanswered. In this paper, we settle several open questions in this area. Specifically, we prove that when the length of a non-uniformly spaced seed is bounded by an exponential function of the seed weight, the seed outperforms strictly the traditional consecutive seed in both (i) the average number of non-overlapping hits and (ii) the asymptotic hit probability. Then, we study the computation of the hit probability of a spaced seed, solving three more open questions: (iii) hit probability computation in a uniform homologous region is NP-hard and (iv) it admits a PTAS; (v) the asymptotic hit probability is computable in exponential time in seed length, independent of the homologous region length.
@cite_59: Large-scale comparison of genomic DNA is of fundamental importance in annotating functional elements of genomes. To perform large comparisons efficiently, BLAST (Methods: Companion Methods Enzymol 266 (1996) 460, J. Mol. Biol. 215 (1990) 403, Nucleic Acids Res. 25(17) (1997) 3389) and other widely used tools use seeded alignment, which compares only sequences that can be shown to share a common pattern or ''seed'' of matching bases. The literature suggests that the choice of seed substantially affects the sensitivity of seeded alignment, but designing and evaluating seeds is computationally challenging. This work addresses the problem of designing a seed to optimize performance of seeded alignment. We give a fast, simple algorithm based on finite automata for evaluating the sensitivity of a seed in a Markov model of ungapped alignments, along with extensions to mixtures and inhomogeneous Markov models. We give intuition and theoretical results on which seeds are good choices. Finally, we describe Mandala, a software tool for seed design, and show that it can be used to improve the sensitivity of alignment in practice.
A good seed exhibits high sensitivity for alignments that model evolutionarily related biosequences, and low sensitivity values for alignments that represent unrelated sequences. The latter property ensures that the seed does not detect too many . Random hits decrease the efficiency of the filtration phase, since they are checked in vain for a significant alignment. An interesting finding was that the PH approach led to an increase in both sensitivity and filtration efficiency, compared to seeds of contiguous matches. Based on the observations in @cite_70 , the advantages of spaced seeds over consecutive seeds have been subsequently evaluated by many authors @cite_59 @cite_46 @cite_58 .