New flexible approaches for multiple sequence alignment.

Abstract

The multiple sequence alignment problem is applicable and important in various fields in molecular biology such as the prediction of three-dimensional structures of proteins and the inference of phylogenetic trees. However, the optimal alignment based on the scoring criterion is not always biologically the most significant alignment. We here propose two flexible and efficient approaches to solve this problem. One approach is to provide many suboptimal alignments as alternatives for the optimal one. It has been considered almost impossible to investigate such suboptimal alignments of more than two sequences because of the enormous size of the problem. We propose techniques for enumeration of suboptimal alignments using the Eppstein algorithm. We also discuss what kind of suboptimal alignment is unnecessary to enumerate and propose an efficient enumeration algorithm to enumerate only necessary alignments. The other approach is parametric analysis. The obtained optimal solution with fixed parameters such as gap penalties is not always the biologically best alignment. Thus, it is required to vary parameters and check how the optimal alignments change. The way to vary parameters has been studied well on the problem of two sequences, but not on the multiple alignment problem because of the difficulty of computing the optimal solution. We propose techniques for this parametric multiple alignment problem and examine the features of alignments obtained by various parametric analyses. For both approaches, this paper performs experiments on various groups of actual protein sequences and examines the efficiency of these algorithms and properties of sequence groups.