Twisted trees and inconsistency of tree estimation when gaps are treated as missing data -- the impact of model mis-specification in distance corrections

Statistically consistent estimation of phylogenetic trees or gene trees is possible if pairwise sequence dissimilarities can be converted to a set of distances that are proportional to the true evolutionary distances. Susko et al. (2004) reported some strikingly broad results about the forms of inconsistency in tree estimation that can arise if corrected distances are not proportional to the true distances. They showed that if the corrected distance is a concave function of the true distance, then inconsistency due to long branch attraction will occur. If these functions are convex, then two "long branch repulsion" trees will be preferred over the true tree -- though these two incorrect trees are expected to be tied as the preferred true. Here we extend their results, and demonstrate the existence of a tree shape (which we refer to as a "twisted Farris-zone" tree) for which a single incorrect tree topology will be guaranteed to be preferred if the corrected distance function is convex. We also report that the standard practice of treating gaps in sequence alignments as missing data is sufficient to produce non-linear corrected distance functions if the substitution process is not independent of the insertion/deletion process. Taken together, these results imply inconsistent tree inference under mild conditions. For example, if some positions in a sequence are constrained to be free of substitutions and insertion/deletion events while the remaining sites evolve with independent substitutions and insertion/deletion events, then the distances obtained by treating gaps as missing data can support an incorrect tree topology even given an unlimited amount of data.Comment: 29 pages, 3 figure

Designing seeds for similarity search in genomic DNA

AbstractLarge-scale comparison of genomic DNA is of fundamental importance in annotating functional elements of genomes. To perform large comparisons efficiently, BLAST (Methods: Companion Methods Enzymol 266 (1996) 460, J. Mol. Biol. 215 (1990) 403, Nucleic Acids Res. 25(17) (1997) 3389) and other widely used tools use seeded alignment, which compares only sequences that can be shown to share a common pattern or “seed’’ of matching bases. The literature suggests that the choice of seed substantially affects the sensitivity of seeded alignment, but designing and evaluating seeds is computationally challenging.This work addresses the problem of designing a seed to optimize performance of seeded alignment. We give a fast, simple algorithm based on finite automata for evaluating the sensitivity of a seed in a Markov model of ungapped alignments, along with extensions to mixtures and inhomogeneous Markov models. We give intuition and theoretical results on which seeds are good choices. Finally, we describe Mandala, a software tool for seed design, and show that it can be used to improve the sensitivity of alignment in practice

A Coverage Criterion for Spaced Seeds and its Applications to Support Vector Machine String Kernels and k-Mer Distances

Spaced seeds have been recently shown to not only detect more alignments, but also to give a more accurate measure of phylogenetic distances (Boden et al., 2013, Horwege et al., 2014, Leimeister et al., 2014), and to provide a lower misclassification rate when used with Support Vector Machines (SVMs) (On-odera and Shibuya, 2013), We confirm by independent experiments these two results, and propose in this article to use a coverage criterion (Benson and Mak, 2008, Martin, 2013, Martin and No{\'e}, 2014), to measure the seed efficiency in both cases in order to design better seed patterns. We show first how this coverage criterion can be directly measured by a full automaton-based approach. We then illustrate how this criterion performs when compared with two other criteria frequently used, namely the single-hit and multiple-hit criteria, through correlation coefficients with the correct classification/the true distance. At the end, for alignment-free distances, we propose an extension by adopting the coverage criterion, show how it performs, and indicate how it can be efficiently computed.Comment: http://online.liebertpub.com/doi/abs/10.1089/cmb.2014.017

Efficient algorithms for the discovery of gapped factors

Background: The discovery of surprisingly frequent patterns is of paramount interest in bioinformatics and computational biology. Among the patterns considered, those consisting of pairs of solid words that co-occur within a prescribed maximum distance-or gapped factors- emerge in a variety of contexts of DNA and protein sequence analysis. A few algorithms and tools have been developed in connection with specific formulations of the problem, however, none can handle comprehensively each of the multiple ways in which the distance between the two terms in a pair may be defined. Results: This paper presents efficient algorithms and tools for the extraction of all pairs of words up to an arbitrarily large length that co-occur surprisingly often in close proximity within a sequence. Whereas the number of such pairs in a sequence of n characters can be Θ(n 4), it is shown that an exhaustive discovery process can be carried out in O(n 2)orO(n 3), depending on the way distance is measured. This is made possible by a prudent combination of properties of pattern maximality and monotonicity of scores, which lead to reduce the number of word pairs to be weighed explicitly, while still producing also the scores attained by any of the pairs not explicitly considered. We applied our approach to the discovery of spaced dyads in DNA sequences. Conclusions: Experiments on biological datasets prove that the method is effective and much faster than exhaustive enumeration of candidate patterns. Software is available freely by academic users via the web interfac

A Coverage Criterion for Spaced Seeds and its Applications to Support Vector Machine String Kernels and k-Mer Distances

Spaced seeds have been recently shown to not only detect more alignments, but also to give a more accurate measure of phylogenetic distances (Boden et al., 2013, Horwege et al., 2014, Leimeister et al., 2014), and to provide a lower misclassification rate when used with Support Vector Machines (SVMs) (On-odera and Shibuya, 2013), We confirm by independent experiments these two results, and propose in this article to use a coverage criterion (Benson and Mak, 2008, Martin, 2013, Martin and No{\'e}, 2014), to measure the seed efficiency in both cases in order to design better seed patterns. We show first how this coverage criterion can be directly measured by a full automaton-based approach. We then illustrate how this criterion performs when compared with two other criteria frequently used, namely the single-hit and multiple-hit criteria, through correlation coefficients with the correct classification/the true distance. At the end, for alignment-free distances, we propose an extension by adopting the coverage criterion, show how it performs, and indicate how it can be efficiently computed.Comment: http://online.liebertpub.com/doi/abs/10.1089/cmb.2014.017

Detection of subtle variations as consensus motifs

AbstractWe address the problem of detecting consensus motifs, that occur with subtle variations, across multiple sequences. These are usually functional domains in DNA sequences such as transcriptional binding factors or other regulatory sites. The problem in its generality has been considered difficult and various benchmark data serve as the litmus test for different computational methods. We present a method centered around unsupervised combinatorial pattern discovery. The parameters are chosen using a careful statistical analysis of consensus motifs. This method works well on the benchmark data and is general enough to be extended to a scenario where the variation in the consensus motif includes indels (along with mutations). We also present some results on detection of transcription binding factors in human DNA sequences

Motif Discovery with Compact Approaches - Design and Applications

In the post-genomic era, the ability to predict the behavior, the function, or the structure of biological entities, as well as interactions among them, plays a fundamental role in the discovery of information to help biologists to explain biological mechanisms. In this context, appropriate characterization of the structures under analysis, and the exploitation of combinatorial properties of sequences, are crucial steps towards the development of efficient algorithms and data structures to be able to perform the analysis of biological sequences. Similarity is a fundamental concept in Biology. Several functional and structural properties, and evolutionary mechanisms, can be predicted comparing new elements with already classified elements, or comparing elements with a similar structure of function to infer the common mechanism that is at the basis of the observed similar behavior. Such elements are commonly called motifs. Comparison-based methods for sequence analysis find their application in several biological contexts, such as identification of transcription factor binding sites, finding structural and functional similarities in proteins, and phylogeny. Therefore the development of adequate methodologies for motif discovery is of paramount interests for several fields in computational biology. In motif discovery in biosequences, it is common to assume that statistically significant candidates are those that are likely to hide some biologically significant property. For this purpose all the possible candidates are ranked according to some statistics on words (frequency, over/under representation, etc.). Then they are presented in output for further inspection by a biologist, who identifies the most promising subsequences, and tests them in laboratory to confirm their biological significance. Therefore, when designing algorithms for motif discovery, besides obviously aim at time and space efficiency, particular attention should be devoted to the output representation. In fact, even considering fixed length strings, the size of the candidate set become exponential if exhaustive enumeration is applied. This is already true when only exact matches are considered as candidate occurrences, and worsen if some kind of variability (for example a fixed number of mismatches is allowed). Alternatively, heuristics could be used, however without the warranty of finding the optimal solution. Computational power of nowadays computers can partially reduce these effects, in particular for short length candidates. However, if the size of the output is too big to be analyzed by human inspection the risk is to provide biologists with very fast, but useless tools. A possible solution relies on compact approaches. Compact approaches are based on the partition of the search space into classes. The classes must be designed in such a way that the score used to rank the candidates has a monotone behavior within each class. This allows the identification of a representative of each class, which is the element with the highest score. Consequently, it suffices to compute, and report in output, the score only for the representatives. In fact, we are guaranteed that for each element that has not been ranked there is another one (the representative of the class it belongs to) that is at least equally significant. The final user can then be presented with an output that has the size of the partition, rather than the size of the candidate space, with obvious advantages for the human-based analysis that follows the computer-based filtering of the pattern discovery algorithm. Compact approaches find applications both in searching and discovery frameworks. They can also be applied to several motif models: exact patterns, patterns with given mismatch distribution, patterns with unknown mismatch distribution, profiles (i.e. matrices), and under both i.i.d. and Markov distributions. The purpose of this chapter is to describe the basis of compact approaches, to provide the readers with the conceptual tools for applying compact approaches to the design of their algorithm for biosequence analysis. Moreover, examples of compact approaches that have been successfully developed for several motif models (e.g. exact words, co-occurrences, words with mismatches, etc) will be explained, and experimental results to discuss their power will be presented

Significance Score of Motifs in Biological Sequences

Available from: http://www.intechopen.com/books/bioinformatics-trends-and-methodologies/significance-score-of-motifs-in-biological-sequence

SOMEA: self-organizing map based extraction algorithm for DNA motif identification with heterogeneous model

<p>Abstract</p> <p>Background</p> <p>Discrimination of transcription factor binding sites (TFBS) from background sequences plays a key role in computational motif discovery. Current clustering based algorithms employ homogeneous model for problem solving, which assumes that motifs and background signals can be equivalently characterized. This assumption has some limitations because both sequence signals have distinct properties.</p> <p>Results</p> <p>This paper aims to develop a Self-Organizing Map (SOM) based clustering algorithm for extracting binding sites in DNA sequences. Our framework is based on a novel intra-node soft competitive procedure to achieve maximum discrimination of motifs from background signals in datasets. The intra-node competition is based on an adaptive weighting technique on two different signal models to better represent these two classes of signals. Using several real and artificial datasets, we compared our proposed method with several motif discovery tools. Compared to SOMBRERO, a state-of-the-art SOM based motif discovery tool, it is found that our algorithm can achieve significant improvements in the average precision rates (i.e., about 27%) on the real datasets without compromising its sensitivity. Our method also performed favourably comparing against other motif discovery tools.</p> <p>Conclusions</p> <p>Motif discovery with model based clustering framework should consider the use of heterogeneous model to represent the two classes of signals in DNA sequences. Such heterogeneous model can achieve better signal discrimination compared to the homogeneous model.</p

Quantum error correction thresholds for non-Abelian Turaev-Viro codes

We consider a two-dimensional quantum memory of qubits on a torus which encode the extended Fibonacci string-net code, and devise strategies for error correction when those qubits are subjected to depolarizing noise. Building on the concept of tube algebras, we construct a set of measurements and of quantum gates which map arbitrary qubit errors to the string-net subspace and allow for the characterization of the resulting error syndrome in terms of doubled Fibonacci anyons. Tensor network techniques then allow to quantitatively study the action of Pauli noise on the string-net subspace. We perform Monte Carlo simulations of error correction in this Fibonacci code, and compare the performance of several decoders. For the case of a fixed-rate sampling depolarizing noise model, we find an error correction threshold of 4.7% using a clustering decoder. To the best of our knowledge, this is the first time that a threshold has been estimated for a two-dimensional error correcting code for which universal quantum computation can be performed within its code space