Detection of recombination in DNA multiple alignments with hidden markov models

CConventional phylogenetic tree estimation methods assume that all sites in a DNA multiple alignment have the same evolutionary history. This assumption is violated in data sets from certain bacteria and viruses due to recombination, a process that leads to the creation of mosaic sequences from different strains and, if undetected, causes systematic errors in phylogenetic tree estimation. In the current work, a hidden Markov model (HMM) is employed to detect recombination events in multiple alignments of DNA sequences. The emission probabilities in a given state are determined by the branching order (topology) and the branch lengths of the respective phylogenetic tree, while the transition probabilities depend on the global recombination probability. The present study improves on an earlier heuristic parameter optimization scheme and shows how the branch lengths and the recombination probability can be optimized in a maximum likelihood sense by applying the expectation maximization (EM) algorithm. The novel algorithm is tested on a synthetic benchmark problem and is found to clearly outperform the earlier heuristic approach. The paper concludes with an application of this scheme to a DNA sequence alignment of the argF gene from four Neisseria strains, where a likely recombination event is clearly detected

A MOSAIC of methods: Improving ortholog detection through integration of algorithmic diversity

Ortholog detection (OD) is a critical step for comparative genomic analysis of protein-coding sequences. In this paper, we begin with a comprehensive comparison of four popular, methodologically diverse OD methods: MultiParanoid, Blat, Multiz, and OMA. In head-to-head comparisons, these methods are shown to significantly outperform one another 12-30% of the time. This high complementarity motivates the presentation of the first tool for integrating methodologically diverse OD methods. We term this program MOSAIC, or Multiple Orthologous Sequence Analysis and Integration by Cluster optimization. Relative to component and competing methods, we demonstrate that MOSAIC more than quintuples the number of alignments for which all species are present, while simultaneously maintaining or improving functional-, phylogenetic-, and sequence identity-based measures of ortholog quality. Further, we demonstrate that this improvement in alignment quality yields 40-280% more confidently aligned sites. Combined, these factors translate to higher estimated levels of overall conservation, while at the same time allowing for the detection of up to 180% more positively selected sites. MOSAIC is available as python package. MOSAIC alignments, source code, and full documentation are available at http://pythonhosted.org/bio-MOSAIC

Estimating seed sensitivity on homogeneous alignments

We address the problem of estimating the sensitivity of seed-based similarity search algorithms. In contrast to approaches based on Markov models [18, 6, 3, 4, 10], we study the estimation based on homogeneous alignments. We describe an algorithm for counting and random generation of those alignments and an algorithm for exact computation of the sensitivity for a broad class of seed strategies. We provide experimental results demonstrating a bias introduced by ignoring the homogeneousness condition

Bayesian regularization of hidden Markov models with an application to bioinformatics

This paper discusses a Bayesian approach to regularizing hidden Markov models and demonstrates an application of this scheme to Bioinformatics

Parameter estimation in pair hidden Markov models

This paper deals with parameter estimation in pair hidden Markov models (pair-HMMs). We first provide a rigorous formalism for these models and discuss possible definitions of likelihoods. The model being biologically motivated, some restrictions with respect to the full parameter space naturally occur. Existence of two different Information divergence rates is established and divergence property (namely positivity at values different from the true one) is shown under additional assumptions. This yields consistency for the parameter in parametrization schemes for which the divergence property holds. Simulations illustrate different cases which are not covered by our results.Comment: corrected typo

Inference with Constrained Hidden Markov Models in PRISM

A Hidden Markov Model (HMM) is a common statistical model which is widely used for analysis of biological sequence data and other sequential phenomena. In the present paper we show how HMMs can be extended with side-constraints and present constraint solving techniques for efficient inference. Defining HMMs with side-constraints in Constraint Logic Programming have advantages in terms of more compact expression and pruning opportunities during inference. We present a PRISM-based framework for extending HMMs with side-constraints and show how well-known constraints such as cardinality and all different are integrated. We experimentally validate our approach on the biologically motivated problem of global pairwise alignment

Conditional Random Field Autoencoders for Unsupervised Structured Prediction

We introduce a framework for unsupervised learning of structured predictors with overlapping, global features. Each input's latent representation is predicted conditional on the observable data using a feature-rich conditional random field. Then a reconstruction of the input is (re)generated, conditional on the latent structure, using models for which maximum likelihood estimation has a closed-form. Our autoencoder formulation enables efficient learning without making unrealistic independence assumptions or restricting the kinds of features that can be used. We illustrate insightful connections to traditional autoencoders, posterior regularization and multi-view learning. We show competitive results with instantiations of the model for two canonical NLP tasks: part-of-speech induction and bitext word alignment, and show that training our model can be substantially more efficient than comparable feature-rich baselines

Developing and applying heterogeneous phylogenetic models with XRate

Modeling sequence evolution on phylogenetic trees is a useful technique in computational biology. Especially powerful are models which take account of the heterogeneous nature of sequence evolution according to the "grammar" of the encoded gene features. However, beyond a modest level of model complexity, manual coding of models becomes prohibitively labor-intensive. We demonstrate, via a set of case studies, the new built-in model-prototyping capabilities of XRate (macros and Scheme extensions). These features allow rapid implementation of phylogenetic models which would have previously been far more labor-intensive. XRate's new capabilities for lineage-specific models, ancestral sequence reconstruction, and improved annotation output are also discussed. XRate's flexible model-specification capabilities and computational efficiency make it well-suited to developing and prototyping phylogenetic grammar models. XRate is available as part of the DART software package: http://biowiki.org/DART .Comment: 34 pages, 3 figures, glossary of XRate model terminolog