Back-translation for discovering distant protein homologies in the presence of frameshift mutations

We developed a novel method to infer distant homology relations of two proteins, that accounts for frameshift and point mutations that may have affected the coding sequences. We design a dynamic programming alignment algorithm over memory-efficient graph representations of the complete set of putative DNA sequences of each protein, with the goal of determining the two putative DNA sequences which have the best scoring alignment under a powerful scoring system designed to reflect the most probable evolutionary process. Our implementation is freely available at http://bioinfo.lifl.fr/path/ webcite.Our approach allows to uncover evolutionary information that is not captured by traditional alignment methods, which is confirmed by biologically significant examples.In protein-coding DNA sequences, frameshift mutations (insertions or deletions of one or more bases) can alter the translation reading frame, affecting all the amino acids encoded from that point forward. Thus, frameshifts produce a drastic change in the resulting protein sequence, preventing any similarity to be visible at the amino acid level. For that reason, classic protein alignment methods, that rely on amino acid comparisons, fail to reveal the proteins' common origins in the case of divergence by frameshift.Consequently, it is natural to handle frameshift mutations at the DNA level, by DNA sequence comparisons. Several papers, including [1-4] reported functional frameshifts discovered using classic alignment tools from the BLAST [5,6] family. In all cases, the DNA sequences were relatively well conserved, which allowed the similarity to remain detectable at the DNA level.However, the divergence may also involve additional base substitutions, that can reduce the similarity of the diverged DNA sequences. It has been shown [7-9] that, in coding DNA, there is a base compositional bias among codon positions, that no longer applies after a reading frame change. A frameshifted coding sequence can be affected b