Abstract
BACKGROUND: Substitution matrices are key parameters for the alignment of two protein sequences, and consequently for most comparative genomics studies. The composition of biological sequences can vary importantly between species and groups of species, and classical matrices such as those in the BLOSUM series fail to accurately estimate alignment scores and statistical significance with sequences sharing marked compositional biases. RESULTS: We present a general and simple methodology to build matrices that are especially fitted to the compositional bias of proteins. Our approach is inspired from the one used to build the BLOSUM matrices and is based on learning substitution and amino acid frequencies on real sequences with the corresponding compositional bias. We applied it to the large scale comparison of Mollicute AT-rich genomes. The new matrix, MOLLI60, was used to predict pairwise orthology relationships, as well as homolog families among 24 Mollicute genomes. We show that this new matrix enables to better discriminate between true and false orthologs and improves the clustering of homologous proteins, with respect to the use of the classical matrix BLOSUM62. CONCLUSIONS: We show in this paper that well-fitted matrices can improve the predictions of orthologous and homologous relationships among proteins with a similar compositional bias. With the ever-increasing number of sequenced genomes, our approach could prove valuable in numerous comparative studies focusing on atypical genomes.