6,910 research outputs found
Probabilistic methods in the analysis of protein interaction networks
Imperial Users onl
Accurate multiple sequence-structure alignment of RNA sequences using combinatorial optimization
Background: The discovery of functional non-coding RNA sequences has led to an increasing interest in algorithms related to RNA analysis. Traditional sequence alignment algorithms, however, fail at computing reliable alignments of low-homology RNA sequences. The spatial conformation of RNA sequences largely determines their function, and therefore RNA alignment algorithms have to take structural information into account. Results: We present a graph-based representation for sequence-structure alignments, which we model as an integer linear program (ILP). We sketch how we compute an optimal or near-optimal solution to the ILP using methods from combinatorial optimization, and present results on a recently published benchmark set for RNA alignments. Conclusions: The implementation of our algorithm yields better alignments in terms of two published scores than the other programs that we tested: This is especially the case with an increasing number of inpu
Structure-function mapping of a heptameric module in the nuclear pore complex.
The nuclear pore complex (NPC) is a multiprotein assembly that serves as the sole mediator of nucleocytoplasmic exchange in eukaryotic cells. In this paper, we use an integrative approach to determine the structure of an essential component of the yeast NPC, the ~600-kD heptameric Nup84 complex, to a precision of ~1.5 nm. The configuration of the subunit structures was determined by satisfaction of spatial restraints derived from a diverse set of negative-stain electron microscopy and protein domain-mapping data. Phenotypic data were mapped onto the complex, allowing us to identify regions that stabilize the NPC's interaction with the nuclear envelope membrane and connect the complex to the rest of the NPC. Our data allow us to suggest how the Nup84 complex is assembled into the NPC and propose a scenario for the evolution of the Nup84 complex through a series of gene duplication and loss events. This work demonstrates that integrative approaches based on low-resolution data of sufficient quality can generate functionally informative structures at intermediate resolution
Covariance models for RNA structure prediction
Many non-coding RNAs are known to play a role in the cell directly linked to their structure. Structure prediction based on the sole sequence is however a challenging task. On the other hand, thanks to the low cost of sequencing technologies, a very large number of homologous
sequences are becoming available for many RNA families. In the protein community, it has emerged in the last decade the idea of exploiting the covariance of mutations within a family to predict the protein structure using the direct- coupling-analysis (DCA) method. The application of DCA to RNA systems has been limited so far. We here perform an assessment of the DCA method on 17 riboswitch families, comparing it with the commonly used mutual information analysis. We also compare different flavors of DCA, including mean-field, pseudo-likelihood, and a proposed stochastic procedure (Boltzmann learning) for solving exactly the DCA inverse problem. Boltzmann learning outperforms the other methods in predicting contacts observed in high resolution crystal structures. In order to enhance the prediction of both RNA secondary and tertiary contacts, we discuss the possibility to include of a number of informed priors in the estimation of the couplings for the DCA statistical model. We observe a systematic improvement of the DCA performance by embedding in the prior distribution the pairing probability matrices calculated using secondary-structure prediction algorithms
Hidden Markov Models for Gene Sequence Classification: Classifying the VSG genes in the Trypanosoma brucei Genome
The article presents an application of Hidden Markov Models (HMMs) for
pattern recognition on genome sequences. We apply HMM for identifying genes
encoding the Variant Surface Glycoprotein (VSG) in the genomes of Trypanosoma
brucei (T. brucei) and other African trypanosomes. These are parasitic protozoa
causative agents of sleeping sickness and several diseases in domestic and wild
animals. These parasites have a peculiar strategy to evade the host's immune
system that consists in periodically changing their predominant cellular
surface protein (VSG). The motivation for using patterns recognition methods to
identify these genes, instead of traditional homology based ones, is that the
levels of sequence identity (amino acid and DNA sequence) amongst these genes
is often below of what is considered reliable in these methods. Among pattern
recognition approaches, HMM are particularly suitable to tackle this problem
because they can handle more naturally the determination of gene edges. We
evaluate the performance of the model using different number of states in the
Markov model, as well as several performance metrics. The model is applied
using public genomic data. Our empirical results show that the VSG genes on T.
brucei can be safely identified (high sensitivity and low rate of false
positives) using HMM.Comment: Accepted article in July, 2015 in Pattern Analysis and Applications,
Springer. The article contains 23 pages, 4 figures, 8 tables and 51
reference
Correlation-Compressed Direct Coupling Analysis
Learning Ising or Potts models from data has become an important topic in
statistical physics and computational biology, with applications to predictions
of structural contacts in proteins and other areas of biological data analysis.
The corresponding inference problems are challenging since the normalization
constant (partition function) of the Ising/Potts distributions cannot be
computed efficiently on large instances. Different ways to address this issue
have hence given size to a substantial methodological literature. In this paper
we investigate how these methods could be used on much larger datasets than
studied previously. We focus on a central aspect, that in practice these
inference problems are almost always severely under-sampled, and the
operational result is almost always a small set of leading (largest)
predictions. We therefore explore an approach where the data is pre-filtered
based on empirical correlations, which can be computed directly even for very
large problems. Inference is only used on the much smaller instance in a
subsequent step of the analysis. We show that in several relevant model classes
such a combined approach gives results of almost the same quality as the
computationally much more demanding inference on the whole dataset. We also
show that results on whole-genome epistatic couplings that were obtained in a
recent computation-intensive study can be retrieved by the new approach. The
method of this paper hence opens up the possibility to learn parameters
describing pair-wise dependencies in whole genomes in a computationally
feasible and expedient manner.Comment: 15 pages, including 11 figure
An Introduction to Programming for Bioscientists: A Python-based Primer
Computing has revolutionized the biological sciences over the past several
decades, such that virtually all contemporary research in the biosciences
utilizes computer programs. The computational advances have come on many
fronts, spurred by fundamental developments in hardware, software, and
algorithms. These advances have influenced, and even engendered, a phenomenal
array of bioscience fields, including molecular evolution and bioinformatics;
genome-, proteome-, transcriptome- and metabolome-wide experimental studies;
structural genomics; and atomistic simulations of cellular-scale molecular
assemblies as large as ribosomes and intact viruses. In short, much of
post-genomic biology is increasingly becoming a form of computational biology.
The ability to design and write computer programs is among the most
indispensable skills that a modern researcher can cultivate. Python has become
a popular programming language in the biosciences, largely because (i) its
straightforward semantics and clean syntax make it a readily accessible first
language; (ii) it is expressive and well-suited to object-oriented programming,
as well as other modern paradigms; and (iii) the many available libraries and
third-party toolkits extend the functionality of the core language into
virtually every biological domain (sequence and structure analyses,
phylogenomics, workflow management systems, etc.). This primer offers a basic
introduction to coding, via Python, and it includes concrete examples and
exercises to illustrate the language's usage and capabilities; the main text
culminates with a final project in structural bioinformatics. A suite of
Supplemental Chapters is also provided. Starting with basic concepts, such as
that of a 'variable', the Chapters methodically advance the reader to the point
of writing a graphical user interface to compute the Hamming distance between
two DNA sequences.Comment: 65 pages total, including 45 pages text, 3 figures, 4 tables,
numerous exercises, and 19 pages of Supporting Information; currently in
press at PLOS Computational Biolog
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