Sequence Database Search Using Jumping Alignments

We describe a new algorithm for amino acid sequence classification and the detection of remote homologues. The rationale is to exploit both vertical and horizontal information of a multiple alignment in a well balanced manner. This is in contrast to established methods like profiles and hidden Markov models which focus on vertical information as they model the columns of the alignment independently. In our setting, we want to select from a given database of "candidate sequences" those proteins that belong to a given superfamily. In order to do so, each candidate sequence is separately tested against a multiple alignment of the known members of the superfamily by means of a new jumping alignment algorithm. This algorithm is an extension of the Smith-Waterman algorithm and computes a local alignment of a single sequence and a multiple alignment. In contrast to traditional methods, however, this alignment is not based on a summary of the individual columns of the multiple alignment. Rather, the candidate sequence at each position is aligned to one sequence of the multiple alignment, called the "reference sequence". In addition, the reference sequence may change within the alignment, while each such jump is penalized. To evaluate the discriminative quality of the jumping alignment algorithm, we compared it to hidden Markov models on a subset of the SCOP database of protein domains. The discriminative quality was assessed by counting the number of false positives that ranked higher than the first true positive (FP-count). For moderate FP-counts above five, the number of successful searches with our method was considerably higher than with hidden Markov models.