Structural Alignment of Pseudoknotted RNA

Abstract

In this paper, we address the problem of discovering novel non-coding RNA (ncRNA) using primary sequence, and secondary structure conservation, focusing on ncRNA families with pseudo-knotted structures. Our main technical result is an efficient algorithm for computing an optimum structural alignment of an RNA sequence against a genomic substring. This algorithm finds two applications. First, by scanning a genome, we can identify novel (homologous) pseudoknotted ncRNA, and second, we can infer the secondary structure of the target aligned sequence. We test an implementation of our algorithm (PAL), and show that it has near-perfect behavior for predicting the structure of many known pseudoknots. Additionally, it can detect the true homologs with high sensitivity and specificity in controlled tests. We also use PAL to search entire viral genome and mouse genome for novel homologs of some viral, and eukaryotic pseudoknots respectively. In each case, we have found strong support for novel homologs.

Structural Alignment of RNA with Complex Pseudoknot Structure

“…Since there is no existing software which available freely for performing structural alignment for complex pseudoknot structures, we follow the evaluation method of Han et al (2008) to compare the performance of our method with BLAST. That is, we want to compare the effectiveness of considering only sequence similarity (based on BLAST) and our method which also consider the structural similarity.…”

“…Recently, Han et al (2008) developed PAL to solve the problem that supports secondary structures with standard pseudoknot of degree k and their algorithm runs in O(kmn k ) where m is the length of the query sequence and n is the length of the target sequence. Their algorithm cannot handle more complex pseudoknot structures such as one with 3 base pairs mutually crossing each other (i.e., any two of them are crossing) as in Figure 1a or the structure allowing recursive pseudoknots (i.e., pseudoknot/regular structures exist within another pseudoknot structure) as in Figure 1b.…”

“…We define a class of pseudoknots called simple non-standard pseudoknot which allows some restricted cases with 3 base pairs mutually crossing each other. Our algorithm can apply to this complex structure using the same time complexity as the PAL algorithm (Han et al, 2008) for standard pseudoknot structure (i.e., O(kmn k ) for degree k). Then, we propose an algorithm to handle a special type of 2-level recursive pseudoknot structure which runs in O(kmn kþ1 ) time.…”

Algorithms for pseudoknot classification

“…Quite a few methods have been developed to solve the structural alignment problem. These methods are usually designed for a specific pseudoknot structure according to the classification given in Han et al [12] and Wong et al [19]. They classified the pseudoknotted structures into five types according to the characteristics and features of the pseudoknots.…”

“…The two popular software tools, RSEARCH [14] and FASTR [21], are designed for structures without pseudoknots. The algorithms developed in [12] handle the structure of standard pseudoknot and embedded standard pseudoknot while the ones in [19] are for the structure of simple non-standard pseudoknot, recursive standard pseudoknot and recursive simple non-standard pseudoknot.…”