Profile Context-Sensitive HMMs for Probabilistic Modeling of Sequences With Complex Correlations

The profile hidden Markov model is a specific type of HMM that is well suited for describing the common features of a set of related sequences. It has been extensively used in computational biology, where it is still one of the most popular tools. In this paper, we propose a new model called the profile context-sensitive HMM. Unlike traditional profile-HMMs, the proposed model is capable of describing complex long-range correlations between distant symbols in a consensus sequence. We also introduce a general algorithm that can be used for finding the optimal state-sequence of an observed symbol sequence based on the given profile-csHMM. The proposed model has an important application in RNA sequence analysis, especially in modeling and analyzing RNA pseudoknots

Fast search of sequences with complex symbol correlations using profile context-sensitive HMMS and pre-screening filters

Recently, profile context-sensitive HMMs (profile-csHMMs) have been proposed which are very effective in modeling the common patterns and motifs in related symbol sequences. Profile-csHMMs are capable of representing long-range correlations between distant symbols, even when these correlations are entangled in a complicated manner. This makes profile-csHMMs an useful tool in computational biology, especially in modeling noncoding RNAs (ncRNAs) and finding new ncRNA genes. However, a profile-csHMM based search is quite slow, hence not practical for searching a large database. In this paper, we propose a practical scheme for making the search speed significantly faster without any degradation in the prediction accuracy. The proposed method utilizes a pre-screening filter based on a profile-HMM, which filters out most sequences that will not be predicted as a match by the original profile-csHMM. Experimental results show that the proposed approach can make the search speed eighty times faster

Computational identification and analysis of noncoding RNAs - Unearthing the buried treasures in the genome

The central dogma of molecular biology states that the genetic information flows from DNA to RNA to protein. This dogma has exerted a substantial influence on our understanding of the genetic activities in the cells. Under this influence, the prevailing assumption until the recent past was that genes are basically repositories for protein coding information, and proteins are responsible for most of the important biological functions in all cells. In the meanwhile, the importance of RNAs has remained rather obscure, and RNA was mainly viewed as a passive intermediary that bridges the gap between DNA and protein. Except for classic examples such as tRNAs (transfer RNAs) and rRNAs (ribosomal RNAs), functional noncoding RNAs were considered to be rare. However, this view has experienced a dramatic change during the last decade, as systematic screening of various genomes identified myriads of noncoding RNAs (ncRNAs), which are RNA molecules that function without being translated into proteins [11], [40]. It has been realized that many ncRNAs play important roles in various biological processes. As RNAs can interact with other RNAs and DNAs in a sequence-specific manner, they are especially useful in tasks that require highly specific nucleotide recognition [11]. Good examples are the miRNAs (microRNAs) that regulate gene expression by targeting mRNAs (messenger RNAs) [4], [20], and the siRNAs (small interfering RNAs) that take part in the RNAi (RNA interference) pathways for gene silencing [29], [30]. Recent developments show that ncRNAs are extensively involved in many gene regulatory mechanisms [14], [17]. The roles of ncRNAs known to this day are truly diverse. These include transcription and translation control, chromosome replication, RNA processing and modification, and protein degradation and translocation [40], just to name a few. These days, it is even claimed that ncRNAs dominate the genomic output of the higher organisms such as mammals, and it is being suggested that the greater portion of their genome (which does not encode proteins) is dedicated to the control and regulation of cell development [27]. As more and more evidence piles up, greater attention is paid to ncRNAs, which have been neglected for a long time. Researchers began to realize that the vast majority of the genome that was regarded as “junk,” mainly because it was not well understood, may indeed hold the key for the best kept secrets in life, such as the mechanism of alternative splicing, the control of epigenetic variations and so forth [27]. The complete range and extent of the role of ncRNAs are not so obvious at this point, but it is certain that a comprehensive understanding of cellular processes is not possible without understanding the functions of ncRNAs [47]

Fast Structural Similarity Search of Noncoding RNAs Based on Matched Filtering of Stem Patterns

Many noncoding RNAs (ncRNAs) have characteristic secondary structures that give rise to complicated base correlations in their primary sequences. Therefore, when performing an RNA similarity search to find new members of a ncRNA family, we need a statistical model - such as the profile- csHMM or the covariance model (CM) - that can effectively describe the correlations between distant bases. However, these models are computationally expensive, making the resulting RNA search very slow. To overcome this problem, various prescreening methods have been proposed that first use a simpler model to scan the database and filter out the dissimilar regions. Only the remaining regions that bear some similarity are passed to a more complex model for closer inspection. It has been shown that the prescreening approach can make the search speed significantly faster at no (or a slight) loss of prediction accuracy. In this paper, we propose a novel prescreening method based on matched filtering of stem patterns. Unlike many existing methods, the proposed method can prescreen the database solely based on structural similarity. The proposed method can handle RNAs with arbitrary secondary structures, and it can be easily incorporated into various search methods that use different statistical models. Furthermore, the proposed approach has a low computational cost, yet very effective for prescreening, as will be demonstrated in the paper

Structural Alignment of RNAs Using Profile-csHMMs and Its Application to RNA Homology Search: Overview and New Results

Systematic research on noncoding RNAs (ncRNAs) has revealed that many ncRNAs are actively involved in various biological networks. Therefore, in order to fully understand the mechanisms of these networks, it is crucial to understand the roles of ncRNAs. Unfortunately, the annotation of ncRNA genes that give rise to functional RNA molecules has begun only recently, and it is far from being complete. Considering the huge amount of genome sequence data, we need efficient computational methods for finding ncRNA genes. One effective way of finding ncRNA genes is to look for regions that are similar to known ncRNA genes. As many ncRNAs have well-conserved secondary structures, we need statistical models that can represent such structures for this purpose. In this paper, we propose a new method for representing RNA sequence profiles and finding structural alignment of RNAs based on profile context-sensitive hidden Markov models (profile-csHMMs). Unlike existing models, the proposed approach can handle any kind of RNA secondary structures, including pseudoknots. We show that profile-csHMMs can provide an effective framework for the computational analysis of RNAs and the identification of ncRNA genes