Abstract
BackgroundIn ribonucleic acid (RNA) molecules whose function depends on their final, folded three-dimensional shape (such as those in ribosomes or spliceosome complexes), the secondary structure, defined by the set of internal basepair interactions, is more consistently conserved than the primary structure, defined by the sequence of nucleotides.ResultsThe research presented here investigates the possibility of applying a progressive, pairwise approach to the alignment of multiple RNA sequences by simultaneously predicting an energy-optimized consensus secondary structure. We take an existing algorithm for finding the secondary structure common to two RNA sequences, Dynalign, and alter it to align profiles of multiple sequences. We then explore the relative successes of different approaches to designing the tree that will guide progressive alignments of sequence profiles to create a multiple alignment and prediction of conserved structure.ConclusionWe have found that applying a progressive, pairwise approach to the alignment of multiple ribonucleic acid sequences produces highly reliable predictions of conserved basepairs, and we have shown how these predictions can be used as constraints to improve the results of a single-sequence structure prediction algorithm. However, we have also discovered that the amount of detail included in a consensus structure prediction is highly dependent on the order in which sequences are added to the alignment (the guide tree), and that if a consensus structure does not have sufficient detail, it is less likely to provide useful constraints for the single-sequence method.
Highlights
IntroductionIn ribonucleic acid (RNA) molecules whose function depends on their final, folded three-dimensional shape (such as those in ribosomes or spliceosome complexes), the secondary structure, defined by the set of internal basepair interactions, is more consistently conserved than the primary structure, defined by the sequence of nucleotides
In ribonucleic acid (RNA) molecules whose function depends on their final, folded three-dimensional shape, the secondary structure, defined by the set of internal basepair interactions, is more consistently conserved than the primary structure, defined by the sequence of nucleotides
The research presented here investigates the possibility of applying a progressive, pairwise approach to the alignment of multiple ribonucleic acid (RNA) sequences, in which the property being aligned is not the primary structure defined by the identity of the nucleotides, but the secondary structure created from base pair interactions
Summary
In ribonucleic acid (RNA) molecules whose function depends on their final, folded three-dimensional shape (such as those in ribosomes or spliceosome complexes), the secondary structure, defined by the set of internal basepair interactions, is more consistently conserved than the primary structure, defined by the sequence of nucleotides. By analyzing the covariance between particular nucleotides across a set of sequences, probable basepairs can be detected by the fact that mutations in the primary sequence will maintain the secondary-structure pairing pattern The combination of these two approaches, applied to the most intensively studied classes of structural RNA molecules (ribosomal RNA and transfer RNA), have resulted in detailed structural models which have been supported by more recent three-dimensional X-ray crystallography analyses [6]. Both approaches are extremely time-consuming, and covariance analyses require large numbers of sequences, including closely related molecules which can be the basis of reliable alignments of the primary sequences. The approach described here focuses on the global alignment and structure prediction of a set of related sequences, using the nearest-neighbour energy model to assess the probable stability of different potential structures
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