Abstract
BackgroundMost of the existing RNA structure prediction programs fold a completely synthesized RNA molecule. However, within the cell, RNA molecules emerge sequentially during the directed process of transcription. Dedicated experiments with individual RNA molecules have shown that RNA folds while it is being transcribed and that its correct folding can also depend on the proper speed of transcription.MethodsThe main aim of this work is to study if and how co-transcriptional folding is encoded within the primary and secondary structure of RNA genes. In order to achieve this, we study the known primary and secondary structures of a comprehensive data set of 361 RNA genes as well as a set of 48 RNA sequences that are known to differ from the originally transcribed sequence units. We detect co-transcriptional folding by defining two measures of directedness which quantify the extend of asymmetry between alternative helices that lie 5' and those that lie 3' of the known helices with which they compete.ResultsWe show with statistical significance that co-transcriptional folding strongly influences RNA sequences in two ways: (1) alternative helices that would compete with the formation of the functional structure during co-transcriptional folding are suppressed and (2) the formation of transient structures which may serve as guidelines for the co-transcriptional folding pathway is encouraged.ConclusionsThese findings have a number of implications for RNA secondary structure prediction methods and the detection of RNA genes.
Highlights
Most of the existing RNA structure prediction programs fold a completely synthesized RNA molecule
Most of the existing computational methods for RNA secondary structure prediction fold an already completely synthesized RNA molecule. This is done either by minimizing its free energy or by maximizing the probability under a model whose parameters can incorporate a variety of different sources of information, e.g. comparative information, free energy and evolutionary information (e.g. [9], TRNASCAN-SE [10], PFOLD [11,12] and QRNA [13]). All of these programs, including those that predict folding pathways by folding an already synthesized RNA sequence [14,15], disregard the effects that co-transcriptional folding may have on the RNA's functional secondary structure
Based on experimental and theoretical investigations, Harlepp et al [21] and Isambert et al [22] found that temporary structures may form during transcription. All these results suggest that temporary secondary structure elements may play an important role in the correct folding of RNA sequences
Summary
Most of the existing RNA structure prediction programs fold a completely synthesized RNA molecule. Most of the existing computational methods for RNA secondary structure prediction fold an already completely synthesized RNA molecule This is done either by minimizing its free energy (e.g. done by MFOLD [1,2,3] and by the programs of the VIENNA package [4,5,6,7,8]) or by maximizing the probability under a model whose parameters can incorporate a variety of different sources of information, e.g. comparative information, free energy and evolutionary information [9], TRNASCAN-SE [10], PFOLD [11,12] and QRNA [13]) All of these programs, including those that predict folding pathways by folding an already synthesized RNA sequence [14,15], disregard the effects that co-transcriptional folding may have on the RNA's functional secondary structure. We call this phenomenon sequential or co-transcriptional folding and call the resulting secondary structure the kinetic structure of the RNA molecule
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