TBI-p-2008-1
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Titel:
Dinucleotide Controlled Null Models for Comparative RNA Gene Prediction.
Author(s):
Tanja Gesell & Stefan Washietl
submitted to:
Abstract:
Background Comparative prediction of RNA structures
can be used to identify functional noncoding RNAs in genomic
screens. It was shown recently by Babak et al. [BMC
Bioinformatics. 8:33] that RNA gene prediction programs can be
biased by the genomic dinucleotide content, in particular those
programs using a thermodynamic folding model including stacking
energies. As a consequence, there is need for
dinucleotide-preserving control strategies to assess the
significance of such predictions. While there have been
randomization algorithms for single sequences for many years, the
problem has remained challenging for multiple alignments and there
is currently no algorithm available.
Results We present a program called SISSId that simulates multiple alignments of a given average dinucleotide content. Meeting additional requirements of an accurate null model, the randomized alignments are on average of the same sequence diversity and preserve local conservation and gap patterns. We make use of a phylogenetic substitution model that includes overlapping dependencies and site-specific rates. Using fast heuristics and a distance based approach, a tree is estimated under this model which is used to guide the simulations. The new algorithm is tested on vertebrate genomic alignments and the effect on RNA structure predictions is studied. In addition, we directly combined the new null model with the RNAalifold consensus folding algorithm giving a new variant of a thermodynamic structure based RNA gene finding program called SISSIz that is not biased by the dinucleotide content.
Conclusions We presented an efficient algorithm to randomize multiple alignments preserving dinucleotide content. It can be used to get more accurate estimates of false positive rates of existing programs, to produce negative controls for the training of machine learning based programs, or as a null model of a standalone RNA gene finding program. Other applications in comparative genomics that require randomization of multiple alignments can be considered.
Availability SISSId/SISSIz are available as open source C code that can be compiled for every major platform and downloaded here: http://www.tbi.univie.ac.at/papers/SUPPLEMENTS/SISSIz
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Last modified: 2008-10-22 12:23:11 fall