This project constitutes an effort to increase the speed of the BLAST algorithms while retaining comparable sensitivity to weak similarities. The approach involves two changes to the basic algorithm. 1) BLAST often finds several alignments involving a single database sequence which, when considered together, are significant. Missing any one of these alignments may compromise the combined result. The new """"""""two-pass"""""""" method uses a higher T parameter for an initial scan of the database. For each database sequence, the discovery of a single alignment with sufficient score triggers a second scan of that sequence using a lower T. This decreases average search time, but retains the ability to find significant results involving several weak alignments. 2) In order to find significant alignments, BLAST first seeks short (typically three-letter) word pairs whose aligned score is at least T. Each such """"""""hit"""""""" is then extended to test whether it is contained in a high-scoring alignment. For the default T value, this extension step consumes the great majority of the processing time used by the old BLAST program. The """"""""two-hit"""""""" method requires the location of two non-overlapping word pairs on the same diagonal, and within a distance A of one another, before either pair is expanded. In order to achieve comparable sensitivity, the threshold parameter T must be lowered, yielding more hits than previously. However, only a small fraction of these hits are expanded; the result is a decrease in the average amount of computation required. This work was presented in March in invited talks at the Second Sandia National Laboratories Workshop on Computational Molecular Biology, in Albuquerque, NM, and at the International Symposium on Theoretical and Computational Genome Research, in Heidelberg, Germany.

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