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Bioinformatics Advance Access published online on September 16, 2008
Bioinformatics, doi:10.1093/bioinformatics/btn495
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© The Author (2008). Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Specific Alignment of Structured RNA: Stochastic Grammars and Sequence Annealing

Robert K. Bradley a, Lior Pachter b,* and Ian Holmes a,c,*

aBiophysics Graduate Group, bDepartment of Mathematics and cDepartment of Bioengineering, University of California, Berkeley, CA 94720, USA

*To whom correspondence should be addressed. Lior Pachter, E-mail: lpachter{at}math.berkeley.edu, ihh{at}berkeley.edu


  Abstract

Motivation: Whole-genome screens suggest that eukaryotic genomes are dense with non-coding RNAs (ncRNAs). We introduce a novel approach to RNA multiple alignment which couples a generative probabilistic model of sequence and structure with an efficient sequence annealing approach for exploring the space of multiple alignments. This leads to a new software program, Stemloc-AMA, that is both accurate and specific in the alignment of multiple related RNA sequences.

Results: When tested on the benchmark datasets BRalibase II and BRalibase 2.1, Stemloc-AMA has comparable sensitivity to and better specificity than the best competing methods. We use a large-scale random-sequence experiment to show that while most alignment programs maximize sensitivity at the expense of specificity, even to the point of giving complete alignments of non-homologous sequences, Stemloc-AMA aligns only sequences with detectable homology and leaves unrelated sequences largely unaligned. Such accurate and specific alignments are crucial for comparative-genomics analysis, from inferring phylogeny to estimating substitution rates across different lineages.

Availability: Stemloc-AMA is available from http://biowiki.org/StemLocAMA as part of the dart software package for sequence analysis.

Contact: lpachter{at}math.berkeley.edu, ihh{at}berkeley.edu

Associate Editor: Prof. Ivo Hofacker

Received on June 20, 2008; revised on September 15, 2008; accepted on September 15, 2008

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