Motivation: Alignment-based methods for sequence analysis have various limitations if large datasets are to be analysed. Therefore, alignment-free approaches have become popular in recent years. One of the best known alignment-free methods is the average common substring approach that defines a distance measure on sequences based on the average length of longest common words between them. Herein, we generalize this approach by considering longest common substrings with k mismatches. We present a greedy heuristic to approximate the length of such k -mismatch substrings, and we describe kmacs , an efficient implementation of this idea based on generalized enhanced suffix arrays.

Results: To evaluate the performance of our approach, we applied it to phylogeny reconstruction using a large number of DNA and protein sequence sets. In most cases, phylogenetic trees calculated with kmacs were more accurate than trees produced with established alignment-free methods that are based on exact word matches. Especially on protein sequences, our method seems to be superior. On simulated protein families, kmacs even outperformed a classical approach to phylogeny reconstruction using multiple alignment and maximum likelihood.

Availability and implementation:  kmacs is implemented in C++, and the source code is freely available at http://kmacs.gobics.de/

Contact:  chris.leimeister@stud.uni-goettingen.de

Supplementary information:  Supplementary data are available at Bioinformatics online.