Dataset Information

A jumping profile Hidden Markov Model and applications to recombination sites in HIV and HCV genomes.

ABSTRACT: Jumping alignments have recently been proposed as a strategy to search a given multiple sequence alignment A against a database. Instead of comparing a database sequence S to the multiple alignment or profile as a whole, S is compared and aligned to individual sequences from A. Within this alignment, S can jump between different sequences from A, so different parts of S can be aligned to different sequences from the input multiple alignment. This approach is particularly useful for dealing with recombination events.We developed a jumping profile Hidden Markov Model (jpHMM), a probabilistic generalization of the jumping-alignment approach. Given a partition of the aligned input sequence family into known sequence subtypes, our model can jump between states corresponding to these different subtypes, depending on which subtype is locally most similar to a database sequence. Jumps between different subtypes are indicative of intersubtype recombinations. We applied our method to a large set of genome sequences from human immunodeficiency virus (HIV) and hepatitis C virus (HCV) as well as to simulated recombined genome sequences.Our results demonstrate that jumps in our jumping profile HMM often correspond to recombination breakpoints; our approach can therefore be used to detect recombinations in genomic sequences. The recombination breakpoints identified by jpHMM were found to be significantly more accurate than breakpoints defined by traditional methods based on comparing single representative sequences.

SUBMITTER: Schultz AK

PROVIDER: S-EPMC1525204 | biostudies-literature | 2006 May

REPOSITORIES: biostudies-literature

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A jumping profile Hidden Markov Model and applications to recombination sites in HIV and HCV genomes.

Schultz Anne-Kathrin AK Zhang Ming M Leitner Thomas T Kuiken Carla C Korber Bette B Morgenstern Burkhard B Stanke Mario M

BMC bioinformatics 20060522

<h4>Background</h4>Jumping alignments have recently been proposed as a strategy to search a given multiple sequence alignment A against a database. Instead of comparing a database sequence S to the multiple alignment or profile as a whole, S is compared and aligned to individual sequences from A. Within this alignment, S can jump between different sequences from A, so different parts of S can be aligned to different sequences from the input multiple alignment. This approach is particularly usefu ...[more]

PMID: 16716226

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Project description:BackgroundRiboswitches are a type of noncoding RNA that regulate gene expression by switching from one structural conformation to another on ligand binding. The various classes of riboswitches discovered so far are differentiated by the ligand, which on binding induces a conformational switch. Every class of riboswitch is characterized by an aptamer domain, which provides the site for ligand binding, and an expression platform that undergoes conformational change on ligand binding. The sequence and structure of the aptamer domain is highly conserved in riboswitches belonging to the same class. We propose a method for fast and accurate identification of riboswitches using profile Hidden Markov Models (pHMM). Our method exploits the high degree of sequence conservation that characterizes the aptamer domain.ResultsOur method can detect riboswitches in genomic databases rapidly and accurately. Its sensitivity is comparable to the method based on the Covariance Model (CM). For six out of ten riboswitch classes, our method detects more than 99.5% of the candidates identified by the much slower CM method while being several hundred times faster. For three riboswitch classes, our method detects 97-99% of the candidates relative to the CM method. Our method works very well for those classes of riboswitches that are characterized by distinct and conserved sequence motifs.ConclusionRiboswitches play a crucial role in controlling the expression of several prokaryotic genes involved in metabolism and transport processes. As more and more new classes of riboswitches are being discovered, it is important to understand the patterns of their intra and inter genomic distribution. Understanding such patterns will enable us to better understand the evolutionary history of these genetic regulatory elements. However, a complete picture of the distribution pattern of riboswitches will emerge only after accurate identification of riboswitches across genomes. We believe that the riboswitch detection method developed in this paper will aid in that process. The significant advantage in terms of speed, of our pHMM-based approach over the method based on CM allows us to scan entire databases (rather than 5'UTRs only) in a relatively short period of time in order to accurately identify riboswitch candidates.

Project description:BackgroundEukaryotic gene regulation is a complex process comprising the dynamic interaction of enhancers and promoters in order to activate gene expression. In recent years, research in regulatory genomics has contributed to a better understanding of the characteristics of promoter elements and for most sequenced model organism genomes there exist comprehensive and reliable promoter annotations. For enhancers, however, a reliable description of their characteristics and location has so far proven to be elusive. With the development of high-throughput methods such as ChIP-seq, large amounts of data about epigenetic conditions have become available, and many existing methods use the information on chromatin accessibility or histone modifications to train classifiers in order to segment the genome into functional groups such as enhancers and promoters. However, these methods often do not consider prior biological knowledge about enhancers such as their diverse lengths or molecular structure.ResultsWe developed enhancer HMM (eHMM), a supervised hidden Markov model designed to learn the molecular structure of promoters and enhancers. Both consist of a central stretch of accessible DNA flanked by nucleosomes with distinct histone modification patterns. We evaluated the performance of eHMM within and across cell types and developmental stages and found that eHMM successfully predicts enhancers with high precision and recall comparable to state-of-the-art methods, and consistently outperforms those in terms of accuracy and resolution.ConclusionseHMM predicts active enhancers based on data from chromatin accessibility assays and a minimal set of histone modification ChIP-seq experiments. In comparison to other 'black box' methods its parameters are easy to interpret. eHMM can be used as a stand-alone tool for enhancer prediction without the need for additional training or a tuning of parameters. The high spatial precision of enhancer predictions gives valuable targets for potential knockout experiments or downstream analyses such as motif search.

Dataset Information

A jumping profile Hidden Markov Model and applications to recombination sites in HIV and HCV genomes.

Publications

A jumping profile Hidden Markov Model and applications to recombination sites in HIV and HCV genomes.

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