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Phylogenetic automata, pruning, and multiple alignment

We present an extension of Felsenstein's algorithm to indel models defined on entire sequences, without the need to condition on one multiple alignment. The algorithm makes use of a generalization from probabilistic substitution matrices to weighted finite-state transducers. Our approach may equivalently be viewed as a probabilistic formulation of progressive multiple sequence alignment, using partial-order graphs to represent ensemble profiles of ancestral sequences. We present a hierarchical stochastic approximation technique which makes this algorithm tractable for alignment analyses of reasonable size.

q-bio.PE↗

Negative Example Aided Transcription Factor Binding Site Search

Computational approaches to transcription factor binding site identification have been actively researched for the past decade. Negative examples have long been utilized in de novo motif discovery and have been shown useful in transcription factor binding site search as well. However, understanding of the roles of negative examples in binding site search is still very limited. We propose the 2-centroid and optimal discriminating vector methods, taking into account negative examples. Cross-validation results on E. coli transcription factors show that the proposed methods benefit from negative examples, outperforming the centroid and position-specific scoring matrix methods. We further show that our proposed methods perform better than a state-of-the-art method. We characterize the proposed methods in the context of the other compared methods and show that, coupled with motif subtype identification, the proposed methods can be effectively applied to a wide range of transcription factors. Finally, we argue that the proposed methods are well-suited for eukaryotic transcription factors as well. Software tools are available at: http://biogrid.engr.uconn.edu/tfbs_search/.

q-bio.GN↗

Models for transcript quantification from RNA-Seq

RNA-Seq is rapidly becoming the standard technology for transcriptome analysis. Fundamental to many of the applications of RNA-Seq is the quantification problem, which is the accurate measurement of relative transcript abundances from the sequenced reads. We focus on this problem, and review many recently published models that are used to estimate the relative abundances. In addition to describing the models and the different approaches to inference, we also explain how methods are related to each other. A key result is that we show how inference with many of the models results in identical estimates of relative abundances, even though model formulations can be very different. In fact, we are able to show how a single general model captures many of the elements of previously published methods. We also review the applications of RNA-Seq models to differential analysis, and explain why accurate relative transcript abundance estimates are crucial for downstream analyses.

q-bio.GN↗

Understanding the Origins of a Pandemic Virus

Understanding the origin of infectious diseases provides scientifically based rationales for implementing public health measures that may help to avoid or mitigate future epidemics. The recent ancestors of a pandemic virus provide invaluable information about the set of minimal genomic alterations that transformed a zoonotic agent into a full human pandemic. Since the first confirmed cases of the H1N1 pandemic virus in the spring of 2009, several hypotheses about the strain's origins have been proposed. However, how, where, and when it first infected humans is still far from clear. The only way to piece together this epidemiological puzzle relies on the collective effort of the international scientific community to increase genomic sequencing of influenza isolates, especially ones collected in the months prior to the origin of the pandemic.

q-bio.PE↗

Unsupervised Classification for Tiling Arrays: ChIP-chip and Transcriptome

Tiling arrays make possible a large scale exploration of the genome thanks to probes which cover the whole genome with very high density until 2 000 000 probes. Biological questions usually addressed are either the expression difference between two conditions or the detection of transcribed regions. In this work we propose to consider simultaneously both questions as an unsupervised classification problem by modeling the joint distribution of the two conditions. In contrast to previous methods, we account for all available information on the probes as well as biological knowledge like annotation and spatial dependence between probes. Since probes are not biologically relevant units we propose a classification rule for non-connected regions covered by several probes. Applications to transcriptomic and ChIP-chip data of Arabidopsis thaliana obtained with a NimbleGen tiling array highlight the importance of a precise modeling and the region classification.

stat.ME↗

Removing System Noise from Comparative Genomic Hybridization Data by Self-Self Analysis

Genomic copy number variation (CNV) is a large source of variation between organisms, and its consequences include phenotypic differences and genetic disorders. CNVs are commonly detected by hybridizing genomic DNA to microarrays of nucleic acid probes. System noise caused by operational and probe performance variability complicates the interpretation of these data. To minimize the distortion of genetic signal by system noise, we have explored the latter in an archive of hybridizations in which no genetic signal is expected. This archive is obtained by comparative genomic hybridization (CGH) of a sample in one channel to the same sample in the other channel, or 'self-self' data. These self-self hybridizations trap a variety of system noise inherent in sample-reference (test) data. Through singular value decomposition (SVD) of self-self data, we have determined the principal components of system noise. Assuming simple linear models of noise generation, the linear correction of test data with self-self data -or 'system normalization'- reduces local and long-range correlations and improves signal-to-noise metrics, yet does not introduce detectable spurious signal. Using this method, 90% of hybridizations displayed improved signal-to-noise ratios with an average increase of 7.0%, due mainly to a reduced median average deviation (MAD). In addition, we have found that principal component loadings correlate with specific probe variables including array coordinates, base composition, and proximity to the 5' ends of genes. The correlation of the principal component loadings with the test data depends on operational variables, such as the temporal order of processing and the localization of individual samples within 96-well plates.

q-bio.QM↗

Matrix eQTL: Ultra fast eQTL analysis via large matrix operations

Expression quantitative trait loci (eQTL) mapping aims to determine genomic regions that regulate gene transcription. Expression QTL is used to study the regulatory structure of normal tissues and to search for genetic factors in complex diseases such as cancer, diabetes, and cystic fibrosis. A modern eQTL dataset contains millions of SNPs and thousands of transcripts measured for hundreds of samples. This makes the analysis computationally complex as it involves independent testing for association for every transcript-SNP pair. The heavy computational burden makes eQTL analysis less popular, often forces analysts to restrict their attention to just a subset of transcripts and SNPs. As larger genotype and gene expression datasets become available, the demand for fast tools for eQTL analysis increases. We present a new method for fast eQTL analysis via linear models, called Matrix eQTL. Matrix eQTL can model and test for association using both linear regression and ANOVA models. The models can include covariates to account for such factors as population structure, gender, and clinical variables. It also supports testing of heteroscedastic models and models with correlated errors. In our experiment on large datasets Matrix eQTL was thousands of times faster than the existing popular software for QTL/eQTL analysis. Matrix eQTL is implemented as both Matlab and R packages and thus can easily be run on Windows, Mac OS, and Linux systems. The software is freely available at the following address: http://www.bios.unc.edu/research/genomic_software/Matrix_eQTL

q-bio.GN↗

Predicting growth fluctuation in network economy

This study presents a method to predict the growth fluctuation of firms interdependent in a network economy. The risk of downward growth fluctuation of firms is calculated from the statistics on Japanese industry.

cs.AI↗

SparseAssembler: de novo Assembly with the Sparse de Bruijn Graph

de Bruijn graph-based algorithms are one of the two most widely used approaches for de novo genome assembly. A major limitation of this approach is the large computational memory space requirement to construct the de Bruijn graph, which scales with k-mer length and total diversity (N) of unique k-mers in the genome expressed in base pairs or roughly (2k+8)N bits. This limitation is particularly important with large-scale genome analysis and for sequencing centers that simultaneously process multiple genomes. We present a sparse de Bruijn graph structure, based on which we developed SparseAssembler that greatly reduces memory space requirements. The structure also allows us to introduce a novel method for the removal of substitution errors introduced during sequencing. The sparse de Bruijn graph structure skips g intermediate k-mers, therefore reducing the theoretical memory space requirement to ~(2k/g+8)N. We have found that a practical value of g=16 consumes approximately 10% of the memory required by standard de Bruijn graph-based algorithms but yields comparable results. A high error rate could potentially derail the SparseAssembler. Therefore, we developed a sparse de Bruijn graph-based denoising algorithm that can remove more than 99% of substitution errors from datasets with a \leq 2% error rate. Given that substitution error rates for the current generation of sequencers is lower than 1%, our denoising procedure is sufficiently effective to safeguard the performance of our algorithm. Finally, we also introduce a novel Dijkstra-like breadth-first search algorithm for the sparse de Bruijn graph structure to circumvent residual errors and resolve polymorphisms.

cs.DS↗

Population Fitness and Genetic Load of Single Nucleotide Polymorphisms Affecting mRNA splicing

Deleterious genetic variants can be evaluated as quantitative traits using information theory-based sequence analysis of recognition sites. To assess the effect of such variants, fitness and genetic load of SNPs which alter binding site affinity are derived from changes in individual information and allele frequencies. Human SNPs that alter mRNA splicing are partitioned according to their genetic load. SNPs with high genetic loads (>0.5) are common in the genome and, in many instances, predicted effects are supported by gene expression studies.

q-bio.GN↗

Quantum Proteomics

We put forward the idea of establishing a novel interdisciplinary field of research at the interface between quantum mechanics and proteomics. The new field, called quantum proteomics, is defined as the large-scale study of the electronic structure of the proteins that define an organism's proteome. The electronic structure of proteins is unveiled with the aid of linear-scaling quantum mechanical calculations. Such calculations provide information about the energy levels of the proteins, the charges of their amino acid side chains, their electrostatic potentials and permanent dipole moments (μ). Since the magnitude of the electric dipole moment of any protein is not null (μ\neq0 Debye), the dipole moment can be employed to characterize the electronic structure of each protein that belongs to an organism's proteome. As an example, we investigate six proteins from the thermophilic bacterium Methanobacterium thermoautotrophicum (Mth) whose atomic structures were characterized by solution NMR spectroscopy.

q-bio.BM↗

Reconstructing Isoform Graphs from RNA-Seq data

Next-generation sequencing (NGS) technologies allow new methodologies for alternative splicing (AS) analysis. Current computational methods for AS from NGS data are mainly focused on predicting splice site junctions or de novo assembly of full-length transcripts. These methods are computationally expensive and produce a huge number of full-length transcripts or splice junctions, spanning the whole genome of organisms. Thus summarizing such data into the different gene structures and AS events of the expressed genes is an hard task. To face this issue in this paper we investigate the computational problem of reconstructing from NGS data, in absence of the genome, a gene structure for each gene that is represented by the isoform graph: we introduce such graph and we show that it uniquely summarizes the gene transcripts. We define the computational problem of reconstructing the isoform graph and provide some conditions that must be met to allow such reconstruction. Finally, we describe an efficient algorithmic approach to solve this problem, validating our approach with both a theoretical and an experimental analysis.

q-bio.GN↗

Estimating Species Trees from Quartet Gene Tree Distributions under the Coalescent Model

In this article we propose a new method, which we name 'quartet neighbor joining', or 'quartet-NJ', to infer an unrooted species tree on a given set of taxa T from empirical distributions of unrooted quartet gene trees on all four-taxon subsets of T. In particular, quartet-NJ can be used to estimate a species tree on T from distributions of gene trees on T. The quartet-NJ algorithm is conceptually very similar to classical neighbor joining, and its statistical consistency under the multispecies coalescent model is proved by a variant of the classical 'cherry picking'-theorem. In order to demonstrate the suitability of quartet-NJ, coalescent processes on two different species trees (on five resp. nine taxa) were simulated, and quartet-NJ was applied to the simulated gene tree distributions. Further, quartet-NJ was applied to quartet distributions obtained from multiple sequence alignments of 28 proteins of nine prokaryotes.

q-bio.PE↗

Similarity of symbolic sequences

A new numerical characterization of symbolic sequences is proposed. The partition of sequence based on Ke and Tong algorithm is a starting point. Algorithm decomposes original sequence into set of distinct subsequences - a patterns. The set of subsequences common for two symbolic sequences (their intersection) is proposed as a measure of similarity between them. The new similarity measure works well for short (of tens letters) sequences and the very long (of hundred thousand letters) as well. When applied to nucleotide or protein sequences may help to trace possible evolutionary of species. As an illustration, similarity of several sets of nucleotide and amino acid sequences is examined.

q-bio.QM↗

A New Biophysical Metric for Interrogating the Information Content in Human Genome Sequence Variation: Proof of Concept

Various studies have shown an association between single nucleotide polymorphisms (SNPs) and common disease. We hypothesize that information encoded in the structure of SNP haploblock variation illumines molecular pathways and cellular mechanisms involved in the regulation of host adaptation to the environment. We developed and utilized the normalized information content (NIC), a novel metric based on SNP haploblock variation. We found that all SNP haploblocks with statistically low information content contained putative transcription factor binding sites and microRNA motifs. We were able to translate a biophysical, mathematical measure of common variants into a deeper understanding of the life sciences through analysis of biochemical patterns associated with SNP haploblock variation. We submit that this new metric, NIC, may be useful in decoding the functional significance of common variation in the human genome and in analyzing the regulation of molecular pathways involved in host adaptation to environmental pathogens.

physics.bio-ph↗

SparseAssembler2: Sparse k-mer Graph for Memory Efficient Genome Assembly

The formal version of our work has been published in BMC Bioinformatics and can be found here: http://www.biomedcentral.com/1471-2105/13/S6/S1 Motivation: To tackle the problem of huge memory usage associated with de Bruijn graph-based algorithms, upon which some of the most widely used de novo genome assemblers have been built, we released SparseAssembler1. SparseAssembler1 can save as much as 90% memory consumption in comparison with the state-of-art assemblers, but it requires rounds of denoising to accurately assemble genomes. In this paper, we introduce a new general model for genome assembly that uses only sparse k-mers. The new model replaces the idea of the de Bruijn graph from the beginning, and achieves similar memory efficiency and much better robustness compared with our previous SparseAssembler1. Results: We demonstrate that the decomposition of reads of all overlapping k-mers, which is used in existing de Bruijn graph genome assemblers, is overly cautious. We introduce a sparse k-mer graph structure for saving sparse k-mers, which greatly reduces memory space requirements necessary for de novo genome assembly. In contrast with the de Bruijn graph approach, we devise a simple but powerful strategy, i.e., finding links between the k-mers in the genome and traversing following the links, which can be done by saving only a few k-mers. To implement the strategy, we need to only select some k-mers that may not even be overlapping ones, and build the links between these k-mers indicated by the reads. We can traverse through this sparse k-mer graph to build the contigs, and ultimately complete the genome assembly. Since the new sparse k-mers graph shares almost all advantages of de Bruijn graph, we are able to adapt a Dijkstra-like breadth-first search algorithm to circumvent sequencing errors and resolve polymorphisms.

cs.DS↗

Emergent Bistability : Effects of Additive and Multiplicative Noise

Positive feedback and cooperativity in the regulation of gene expression are generally considered to be necessary for obtaining bistable expression states. Recently, a novel mechanism of bistability termed emergent bistability has been proposed which involves only positive feedback and no cooperativity in the regulation. An additional positive feedback loop is effectively generated due to the inhibition of cellular growth by the synthesized proteins. The mechanism, demonstrated for a synthetic circuit, may be prevalent in natural systems also as some recent experimental results appear to suggest. In this paper, we study the effects of additive and multiplicative noise on the dynamics governing emergent bistability. The calculational scheme employed is based on the Langevin and Fokker-Planck formalisms. The steady state probability distributions of protein levels and the mean first passage times are computed for different noise strengths and system parameters. In the region of bistability, the bimodal probability distribution is shown to be a linear combination of a lognormal and a Gaussian distribution. The variances of the individual distributions and the relative weights of the distributions are further calculated for varying noise strengths and system parameters. The experimental relevance of the model results is also pointed out.

q-bio.QM↗

Note on expected internode distances for gene trees in species trees

In a recent paper on 'Estimating Species Trees from Unrooted Gene Trees' Liu and Yu observe that the distance matrix on the underlying taxon set, which is built up from expected internode distances on gene trees under the multispecies coalescent, is tree-like, and that the underlying additive tree has the same topology as the true species tree. Hence they suggest to use (observed) average internode distances on gene trees as an input for the neighbor joining algorithm to estimate the underlying species tree in a statistically consistent way. In this note we give a rigorous proof of their above mentioned observation.

q-bio.PE↗