Homology search with fragmented nucleic acid sequence patterns

The comprehensive annotation of non-coding RNAs in newly sequenced genomes is still a largely unsolved problem because many functional RNAs exhibit not only poorly conserved sequences but also large variability in structure. In many cases, such as Y RNAs, vault RNAs, or telomerase RNAs, sequences differ by large insertions or deletions and have only a few small sequence patterns in common. Here we present fragrep2, a purely sequence-based approach to detect such patterns in complete genomes. A fragrep2 pattern consists of an ordered list of position-specific weight matrices (PWMs) describing short, approximately conserved sequence elements, that are separated by intervals of non-conserved regions of bounded length. The program uses a fractional programming approach to align the PWMs to genomic DNA in order to allow for a bounded number of insertions and deletions in the patterns. These patterns are then combined to significant combinations of PWMs. At this step, a subset of PWMs may be deleted, i.e., have no match in the current region of the genome. The program furthermore estimates p- and E-values for the matches. We apply fragrep2 to homology searches for RNase MRP, unveiling two previously unidentified matches as well as reproducing the results of two previous surveys. Furthermore, we complement the picture of vertebrate vault RNAs, a class of ncRNAs that has not received much attention so far.