RNA secondary structure prediction from multi-aligned sequences

It has been well accepted that the RNA secondary structures of most functional non-coding RNAs (ncRNAs) are closely related to their functions and are conserved during evolution. Hence, prediction of conserved secondary structures from evolutionarily related sequences is one important task in RNA bioinformatics; the methods are useful not only to further functional analyses of ncRNAs but also to improve the accuracy of secondary structure predictions and to find novel functional RNAs from the genome. In this review, I focus on common secondary structure prediction from a given aligned RNA sequence, in which one secondary structure whose length is equal to that of the input alignment is predicted. I systematically review and classify existing tools and algorithms for the problem, by utilizing the information employed in the tools and by adopting a unified viewpoint based on maximum expected gain (MEG) estimators. I believe that this classification will allow a deeper understanding of each tool and provide users with useful information for selecting tools for common secondary structure predictions.Comment: A preprint of an invited review manuscript that will be published in a chapter of the book `Methods in Molecular Biology'. Note that this version of the manuscript may differ from the published versio

A new procedure to analyze RNA non-branching structures

RNA structure prediction and structural motifs analysis are challenging tasks in the investigation of RNA function. We propose a novel procedure to detect structural motifs shared between two RNAs (a reference and a target). In particular, we developed two core modules: (i) nbRSSP_extractor, to assign a unique structure to the reference RNA encoded by a set of non-branching structures; (ii) SSD_finder, to detect structural motifs that the target RNA shares with the reference, by means of a new score function that rewards the relative distance of the target non-branching structures compared to the reference ones. We integrated these algorithms with already existing software to reach a coherent pipeline able to perform the following two main tasks: prediction of RNA structures (integration of RNALfold and nbRSSP_extractor) and search for chains of matches (integration of Structator and SSD_finder)

LaRA 2: parallel and vectorized program for sequence–structure alignment of RNA sequences

Background The function of non-coding RNA sequences is largely determined by their spatial conformation, namely the secondary structure of the molecule, formed by Watson–Crick interactions between nucleotides. Hence, modern RNA alignment algorithms routinely take structural information into account. In order to discover yet unknown RNA families and infer their possible functions, the structural alignment of RNAs is an essential task. This task demands a lot of computational resources, especially for aligning many long sequences, and it therefore requires efficient algorithms that utilize modern hardware when available. A subset of the secondary structures contains overlapping interactions (called pseudoknots), which add additional complexity to the problem and are often ignored in available software. Results We present the SeqAn-based software LaRA 2 that is significantly faster than comparable software for accurate pairwise and multiple alignments of structured RNA sequences. In contrast to other programs our approach can handle arbitrary pseudoknots. As an improved re-implementation of the LaRA tool for structural alignments, LaRA 2 uses multi-threading and vectorization for parallel execution and a new heuristic for computing a lower boundary of the solution. Our algorithmic improvements yield a program that is up to 130 times faster than the previous version. Conclusions With LaRA 2 we provide a tool to analyse large sets of RNA secondary structures in relatively short time, based on structural alignment. The produced alignments can be used to derive structural motifs for the search in genomic databases

LaRA 2: parallel and vectorized program for sequence–structure alignment of RNA sequences

Background The function of non-coding RNA sequences is largely determined by their spatial conformation, namely the secondary structure of the molecule, formed by Watson–Crick interactions between nucleotides. Hence, modern RNA alignment algorithms routinely take structural information into account. In order to discover yet unknown RNA families and infer their possible functions, the structural alignment of RNAs is an essential task. This task demands a lot of computational resources, especially for aligning many long sequences, and it therefore requires efficient algorithms that utilize modern hardware when available. A subset of the secondary structures contains overlapping interactions (called pseudoknots), which add additional complexity to the problem and are often ignored in available software. Results We present the SeqAn-based software LaRA 2 that is significantly faster than comparable software for accurate pairwise and multiple alignments of structured RNA sequences. In contrast to other programs our approach can handle arbitrary pseudoknots. As an improved re-implementation of the LaRA tool for structural alignments, LaRA 2 uses multi-threading and vectorization for parallel execution and a new heuristic for computing a lower boundary of the solution. Our algorithmic improvements yield a program that is up to 130 times faster than the previous version. Conclusions With LaRA 2 we provide a tool to analyse large sets of RNA secondary structures in relatively short time, based on structural alignment. The produced alignments can be used to derive structural motifs for the search in genomic databases

Computational analysis of noncoding RNAs

Noncoding RNAs have emerged as important key players in the cell. Understanding their surprisingly diverse range of functions is challenging for experimental and computational biology. Here, we review computational methods to analyze noncoding RNAs. The topics covered include basic and advanced techniques to predict RNA structures, annotation of noncoding RNAs in genomic data, mining RNA-seq data for novel transcripts and prediction of transcript structures, computational aspects of microRNAs, and database resources.Austrian Science Fund (Schrodinger Fellowship J2966-B12)German Research Foundation (grant WI 3628/1-1 to SW)National Institutes of Health (U.S.) (NIH award 1RC1CA147187

Homology ­modeling of complex structural RNAs

National audienceAligning macromolecules such as proteins, DNAs and RNAs in order to reveal, or conversely exploit, their functional homology is a classic challenge in bioinformatics, with far­reaching applications in structure modelling and genome annotations. In the specific context of complex RNAs, featuring pseudoknots, multiple interactions and non­canonical base pairs, multiple algorithmic solutions and tools have been proposed for the structure/sequence alignment problem. However, such tools are seldom used in practice, due in part to their extreme computational demands, and because of their inability to support general types of structures. Recently, a general parameterized algorithm based on tree decomposition of the query structure has been designed by Rinaudo et al. We present an implementation of the algorithm within a tool named LiCoRNA. We compare it against state­of­the­art algorithms. We show that it both gracefully specializes into a practical algorithm for simple classes pseudoknot, and offers a general solution for complex pseudoknots, which are explicitly out­of­reach of competing softwares

The Rna Newton Polytope And Learnability Of Energy Parameters

Computational RNA secondary structure prediction has been a topic of much research interest for several decades now. Despite all the progress made in the field, even the state-of-the-art algorithms do not provide satisfying results, and the accuracy of output is limited for all the existent tools. Very complex energy models, different parameter estimation methods, and recent machine learning approaches had not been the answer for this problem. We believe that the first step to achieve results with high quality is to use the energy model with the potential for predicting accurate output. Hence, it is necessary to have a systematic way to analyze the suitability of an energy model. We introduced the notion of learnability to measure this suitability. A learnable energy model has at least one subset of parameters that can render every known RNA to date the minimum free energy structure, which means 100% accuracy. We also found the necessary condition for a model to be learnable and implemented the dynamic programming based algorithm to asses this condition for a set of RNAs. This algorithm computes the convex hull of all possible feature vectors for a sequence. With the partition function as a polynomial, this convex hull is also the Newton polytope of the partition function. To the best of our knowledge, this is the first systematic approach for evaluating the inherent capability of an energy model

Data mining in computational proteomics and genomics

This dissertation addresses data mining in bioinformatics by investigating two important problems, namely peak detection and structure matching. Peak detection is useful for biological pattern discovery while structure matching finds many applications in clustering and classification. The first part of this dissertation focuses on elastic peak detection in 2D liquid chromatographic mass spectrometry (LC-MS) data used in proteomics research. These data can be modeled as a time series, in which the X-axis represents time points and the Y-axis represents intensity values. A peak occurs in a set of 2D LC-MS data when the sum of the intensity values in a sliding time window exceeds a user-determined threshold. The elastic peak detection problem is to locate all peaks across multiple window sizes of interest in the dataset. A new method, called PeakID, is proposed in this dissertation, which solves the elastic peak detection problem in 2D LC-MS data without yielding any false negative. PeakID employs a novel data structure, called a Shifted Aggregation Tree or AggTree for short, to find the different peaks in the dataset. This method works by first constructing an AggTree in a bottom-up manner from the dataset, and then searching the AggTree for the peaks in a top-down manner. PeakID uses a state-space algorithm to find the topology and structure of an efficient AggTree. Experimental results demonstrate the superiority of the proposed method over other methods on both synthetic and real-world data. The second part of this dissertation focuses on RNA pseudoknot structure matching and alignment. RNA pseudoknot structures play important roles in many genomic processes. Previous methods for comparative pseudoknot analysis mainly focus on simultaneous folding and alignment of RNA sequences. Little work has been done to align two known RNA secondary structures with pseudoknots taking into account both sequence and structure information of the two RNAs. A new method, called RKalign, is proposed in this dissertation for aligning two known RNA secondary structures with pseudoknots. RKalign adopts the partition function methodology to calculate the posterior log-odds scores of the alignments between bases or base pairs of the two RNAs with a dynamic programming algorithm. The posterior log-odds scores are then used to calculate the expected accuracy of an alignment between the RNAs. The goal is to find an optimal alignment with the maximum expected accuracy. RKalign employs a greedy algorithm to achieve this goal. The performance of RKalign is investigated and compared with existing tools for RNA structure alignment. An extension of the proposed method to multiple alignment of pseudoknot structures is also discussed. RKalign is implemented in Java and freely accessible on the Internet. As more and more pseudoknots are revealed, collected and stored in public databases, it is anticipated that a tool like RKalign will play a significant role in data comparison, annotation, analysis, and retrieval in these databases