Towards Long-Range RNA Structure Prediction in Eukaryotic Genes.

Dmitri Pervouchine

doi:10.3390/genes9060302

Abstract

The ability to form an intramolecular structure plays a fundamental role in eukaryotic RNA biogenesis. Proximate regions in the primary transcripts fold into a local secondary structure, which is then hierarchically assembled into a tertiary structure that is stabilized by RNA-binding proteins and long-range intramolecular base pairings. While the local RNA structure can be predicted reasonably well for short sequences, long-range structure at the scale of eukaryotic genes remains problematic from the computational standpoint. The aim of this review is to list functional examples of long-range RNA structures, to summarize current comparative methods of structure prediction, and to highlight their advances and limitations in the context of long-range RNA structures. Most comparative methods implement the “first-align-then-fold” principle, i.e., they operate on multiple sequence alignments, while functional RNA structures often reside in non-conserved parts of the primary transcripts. The opposite “first-fold-then-align” approach is currently explored to a much lesser extent. Developing novel methods in both directions will improve the performance of comparative RNA structure analysis and help discover novel long-range structures, their higher-order organization, and RNA–RNA interactions across the transcriptome.

Highlights

The structure of RNA molecules is believed to comprise two levels: the secondary structure, which is formed by proximate regions in the primary sequence, and the tertiary structure, which includes long-range interactions [6]
The secondary structure is local, i.e., it forms between nearby sequences during Pol II elongation; in contrast, the tertiary structure is global, i.e., it builds from pre-formed helical domains of the local structure
Our ability to predict eukaryotic pre-mRNA structure is biased towards local structures, while the prediction of long-range RNA structure remains problematic from the computational point of view

Summary

Introduction

The secondary structure is local, i.e., it forms between nearby sequences during Pol II elongation; in contrast, the tertiary structure is global, i.e., it builds from pre-formed helical domains of the local structure. Both terms refer to the secondary level of structure organization, in the sense that they both constitute residue interactions that are stabilized by stacking energies. Our ability to predict eukaryotic pre-mRNA structure is biased towards local structures, while the prediction of long-range RNA structure remains problematic from the computational point of view. The second part is not designed to be a complete review of all RNA structure predictions methods; I cite only the selected computational works that contain the most references to other papers in the field

Instances of Long-Range RNA Structure

Predicting Long-Range RNA Structure

Concluding Remarks

Methods