CHAPAO: Likelihood and hierarchical reference-based representation of biomolecular sequences and applications to compressing multiple sequence alignments

The eXtensible Markup Language (XML) provides a powerful and flexible means of encoding and exchanging data. As it turns out, its main advantage as an encoding format (namely, its requirement that all open and close markup tags are present and properly balanced) yield also one of its main disadvantages: verbosity. XML-conscious compression techniques seek to overcome this drawback. Many of these techniques first separate XML structure from the document content, and then compress each independently. Further compression gains can be realized by identifying and compressing together document content that is highly similar, thereby amortizing the storage costs of auxiliary information required by the chosen compression algorithm. Additionally, the proper choice of compression algorithm is an important factor not only for the achievable compression gain, but also for access performance. Hence, choosing a compression configuration that optimizes compression gain requires one to determine (1) a partitioning strategy for document content, and (2) the best available compression algorithm to apply to each set within this partition. In this paper, we show that finding an optimal compression configuration with respect to compression gain is an NP-hard optimization problem. This problem remains intractable even if one considers a single compression algorithm for all content. We also describe an approximation algorithm for selecting a partitioning strategy for document content based on the branch-and-bound paradigm.

With the development of new sequencing techniques, whole genomes of many species have become available. This huge amount of data gives rise to new opportunities and challenges. These new sequences provide valuable information on relationships among species, e.g. genome recombination and conservation. One of the principal ways to investigate such information is multiple sequence alignment (MSA). Currently, there is large amount of MSA data on the internet, such as the UCSC genome database, but how to effectively use this information to solve classical and new problems is still an area lacking of exploration. In this thesis, we explored how to use this information in four problems, i.e. sequence orthology search problem, multiple alignment improvement problem, short read mapping problem, and genome rearrangement inference problem. For the first problem, we developed a EM algorithm to iteratively align a query with a multiple alignment database with the information from a phylogeny relating the query species and the species in the multiple alignment. We also infer the query's location in the phylogeny. We showed that by doing alignment and phylogeny inference together, we can improve the accuracies for both problems. For the second problem, we developed an optimization algorithm to iteratively refine the multiple alignment quality. Experiment results showed our algorithm is very stable in term of resulting alignments. The results showed that our method is more accurate than existing methods, i.e. Mafft, Clustal-O, and Mavid, on test data from three sets of species from the UCSC genome database. For the third problem, we developed a model, PhyMap, to align a read to a multiple alignment allowing mismatches and indels. PhyMap computes local alignments of a query sequence against a fixed multiple-genome alignment of closely related species. PhyMap uses a known phylogenetic tree on the species in the multiple alignment to improve the quality of its computed alignments while also estimating the placement of the query on this tree. Both theoretical computation and experiment results show that our model can differentiate between orthologous and paralogous alignments better than other popular short read mapping tools (BWA, BOWTIE and BLAST). For the fourth problem, we gave a simple genome recombination model which can express insertions, deletions, inversions, translocations and inverted translocations on aligned genome segments. We also developed an MCMC algorithm to infer the order of the query segments. We proved that using any Euclidian metrics to measure distance between two sequence orders in the tree optimization goal function will lead to a degenerated solution where the inferred order will be the order of one of the leaf nodes. We also gave a graph-based formulation of the problem which can represent the probability distribution of the order of the query sequences.

The standard approach for constructing a phylogenetic tree from a set of sequences consists of two key stages. First, a multiple sequence alignment (MSA) of the sequences is computed. The aligned data are then used to reconstruct the phylogenetic tree. The accuracy of the resulting tree heavily relies on the quality of the MSA. The quality of the popularly used progressive sequence alignment depends on a guide tree, which determines the order of aligning sequences. Most MSA methods use pairwise comparisons to generate a distance matrix and reconstruct the guide tree. However, when dealing with highly diverged sequences, constructing a good guide tree is challenging. In this work, we propose an alternative approach using three-way dynamic programming alignment to generate the distance matrix and the guide tree. This three-way alignment incorporates information from additional sequences to compute evolutionary distances more accurately. Using simulated datasets on two symmetric and asymmetric trees, we compared MAFFT with its default guide tree with MAFFT with a guide tree produced using the three-way alignment. We found that (1) the three-way alignment can reconstruct better guide trees than those from the most accurate options of MAFFT, and (2) the better guide tree, on average, leads to more accurate phylogenetic reconstruction. However, the improvement over the L-INS-i option of MAFFT is small, attesting to the excellence of the alignment quality of MAFFT. Surprisingly, the two criteria for choosing the best MSA (phylogenetic accuracy and sum-of-pair score) conflict with each other.

Background:Currently available methods to predict splice sites are mainly based on the independent and progressive alignment of transcript data (mostly ESTs) to the genomic sequence. Apart from often being computationally expensive, this approach is vulnerable to several problems – hence the need to develop novel strategies.Results:We propose a method, based on a novel multiple genome-EST alignment algorithm, for the detection of splice sites. To avoid limitations of splice sites prediction (mainly, over-predictions) due to independent single EST alignments to the genomic sequence our approach performs a multiple alignment of transcript data to the genomic sequence based on the combined analysis of all available data. We recast the problem of predicting constitutive and alternative splicing as an optimization problem, where the optimal multiple transcript alignment minimizes the number of exons and hence of splice site observations.We have implemented a splice site predictor based on this algorithm in the software tool ASPIC (Alternative Splicing PredICtion). It is distinguished from other methods based on BLAST-like tools by the incorporation of entirely new ad hoc procedures for accurate and computationally efficient transcript alignment and adopts dynamic programming for the refinement of intron boundaries. ASPIC also provides the minimal set of non-mergeable transcript isoforms compatible with the detected splicing events. The ASPIC web resource is dynamically interconnected with the Ensembl and Unigene databases and also implements an upload facility.Conclusion:Extensive bench marking shows that ASPIC outperforms other existing methods in the detection of novel splicing isoforms and in the minimization of over-predictions. ASPIC also requires a lower computation time for processing a single gene and an EST cluster. The ASPIC web resource is available at .

SummaryPRALINE 2 is a toolkit for custom multiple sequence alignment workflows. It can be used to incorporate sequence annotations, such as secondary structure or (DNA) motifs, into the alignment scoring, as well as to customize many other aspects of a progressive multiple alignment workflow.Availability and implementationPRALINE 2 is implemented in Python and available as open source software on GitHub: https://github.com/ibivu/PRALINE/.

The idea that DNA encodes the human body is uncontested. Everything about a person, including behaviour and physical characteristics, is influenced by genetic information. Genomic data is a rich source of information when it is analysed, genomic data has a significant potential for use in disease diagnosis. Despite the fact that One size does not fit all, the medical advice is usually generic. The intelligent machine may provide us with additional human body knowledge on the contrary to build intelligent robots. The ongoing development of genomic data is either beneficial for engineering as well as medical research. Our search for personalised medicine may have a solution in the overlapping fields of engineering and medicine. The introduction of new emergent multimedia applications with an increase in demand and consumption of genetic data, as well as the invasion of digital media into every aspect of diagnosis and prognosis, are compelling new challenges for next-generation sequencing. The processing of genomic data is intended to meet hitheito unrecognised requirements, including compression, robustness, security, unambiguity, and the prediction of future anomalies, in addition to delivering individualised treatment. Deep neural network based deep learning has been intensively researched in recent years as one of the possible methods for overcoming these difficulties. Because digital data must be maintained effectively, with very high quality, and shouldn’t be easily modified by computer standards. The goal is to develop a safe genome compression method that significantly outperforms existing sequencing methods in terms of all performance parameters.

In clinical genomics, the continuous evolution of bioinformatic algorithms and sequencing platforms makes it beneficial to store patients’ complete aligned genomic data in addition to variant calls relative to a reference sequence. Due to the large size of human genome sequence data files (varying from 30 GB to 200 GB depending on coverage), two major challenges facing genomics laboratories are the costs of storage and the efficiency of the initial data processing. In addition, privacy of genomic data is becoming an increasingly serious concern, yet no standard data storage solutions exist that enable compression, encryption, and selective retrieval. Here we present a privacy-preserving solution named SECRAM (Selective retrieval on Encrypted and Compressed Reference-oriented Alignment Map) for the secure storage of compressed aligned genomic data. Our solution enables selective retrieval of encrypted data and improves the efficiency of downstream analysis (e.g., variant calling). Compared with BAM, the de facto standard for storing aligned genomic data, SECRAM uses 18% less storage. Compared with CRAM, one of the most compressed nonencrypted formats (using 34% less storage than BAM), SECRAM maintains efficient compression and downstream data processing, while allowing for unprecedented levels of security in genomic data storage. Compared with previous work, the distinguishing features of SECRAM are that (1) it is position-based instead of read-based, and (2) it allows random querying of a subregion from a BAM-like file in an encrypted form. Our method thus offers a space-saving, privacy-preserving, and effective solution for the storage of clinical genomic data.

Chapter 1 - Introduction

Motivation: Recent breakthroughs in protein residue–residue contact prediction have made reliable de novo prediction of protein structures possible. The key was to apply statistical methods that can distinguish direct couplings between pairs of columns in a multiple sequence alignment from merely correlated pairs, i.e. to separate direct from indirect effects. Two classes of such methods exist, either relying on regularized inversion of the covariance matrix or on pseudo-likelihood maximization (PLM). Although PLM-based methods offer clearly higher precision, available tools are not sufficiently optimized and are written in interpreted languages that introduce additional overheads. This impedes the runtime and large-scale contact prediction for larger protein families, multi-domain proteins and protein–protein interactions.Results: Here we introduce CCMpred, our performance-optimized PLM implementation in C and CUDA C. Using graphics cards in the price range of current six-core processors, CCMpred can predict contacts for typical alignments 35–113 times faster and with the same precision as the most accurate published methods. For users without a CUDA-capable graphics card, CCMpred can also run in a CPU mode that is still 4–14 times faster. Thanks to our speed-ups (http://dictionary.cambridge.org/dictionary/british/speed-up) contacts for typical protein families can be predicted in 15–60 s on a consumer-grade GPU and 1–6 min on a six-core CPU.Availability and implementation: CCMpred is free and open-source software under the GNU Affero General Public License v3 (or later) available at https://bitbucket.org/soedinglab/ccmpredContact: johannes.soeding@mpibpc.mpg.deSupplementary information: Supplementary data are available at Bioinformatics online.

Alignment of biological sequences is one of the most important and challenging tasks in computational biology and bioinformatics and is inherently complex. The algorithmic solutions are characterized by huge computational and memory requirements. We present an approach to biosequences alignment, that uses a genetic algorithm to search the solution space. By converting a given biomolecular sequence into an optimal or near optimal search problem in the solution space, the genetic algorithm efficiently and robustly finds the solution for the multiple sequence alignment. Our approach is different from previous similar approaches in the sense that it allows pairwise alignment in each generation and does not utilize dynamic programming at any stage. This paper presents our approach and demonstrates its performances with experiments on real DNA datasets.

Although recent advanced sequencing technologies have improved the resolution of genomic and proteomic data to better characterize molecular phenotypes, efficient computational tools to analyze and interpret large-scale omic data are still needed. To address this, we have developed a network-based bioinformatic tool called Ollivier-Ricci curvature for omics (ORCO). ORCO incorporates omics data and a network describing biological relationships between the genes or proteins and computes Ollivier-Ricci curvature (ORC) values for individual interactions. ORC is an edge-based measure that assesses network robustness. It captures functional cooperation in gene signaling using a consistent information-passing measure, which can help investigators identify therapeutic targets and key regulatory modules in biological systems. ORC has identified novel insights in multiple cancer types using genomic data and in neurodevelopmental disorders using brain imaging data. This tool is applicable to any data that can be represented as a network. ORCO is an open-source Python package and is publicly available on GitHub at https://github.com/aksimhal/ORC-Omics.

Multiple sequence alignment (MSA) is the basis for a wide range of comparative sequence analyses from molecular phylogenetics to 3D structure prediction. Sophisticated algorithms have been developed for sequence alignment, but in practice, many errors can be expected and extensive portions of the MSA are unreliable. Hence, it is imperative to understand and characterize the various sources of errors in MSAs and to quantify site-specific alignment confidence. In this paper, we show that uncertainties in the guide tree used by progressive alignment methods are a major source of alignment uncertainty. We use this insight to develop a novel method for quantifying the robustness of each alignment column to guide tree uncertainty. We build on the widely used bootstrap method for perturbing the phylogenetic tree. Specifically, we generate a collection of trees and use each as a guide tree in the alignment algorithm, thus producing a set of MSAs. We next test the consistency of every column of the MSA obtained from the unperturbed guide tree with respect to the set of MSAs. We name this measure the "GUIDe tree based AligNment ConfidencE" (GUIDANCE) score. Using the Benchmark Alignment data BASE benchmark as well as simulation studies, we show that GUIDANCE scores accurately identify errors in MSAs. Additionally, we compare our results with the previously published Heads-or-Tails score and show that the GUIDANCE score is a better predictor of unreliably aligned regions.

Uncompressed form of the digital images are needed a very large storage capacity amount, as a consequence requires large communication bandwidth for data transmission over the network. Image compression techniques not only minimize the image storage space but also preserve the quality of image. This paper reveal image compression technique which uses distinct image coding scheme based on wavelet transform that combined effective types of compression algorithms for further compression. EZW and SPIHT algorithms are types of significant compression techniques that obtainable for lossy image compression algorithms. The EZW coding is a worthwhile and simple efficient algorithm. SPIHT is an most powerful technique that utilize for image compression depend on the concept of coding set of wavelet coefficients as zero trees. The proposed compression algorithm that combined dual image compression techniques (DICT) invest an excellent features from each methods, which then produce promising technique for still image compression through minimize bits number that required to represent the input image, to the degree allowed without significant impact on quality of reconstructed image.
 The experimental results present that DICT will improve the image compression efficiency between 8 to 24%, and will result high performance of metrics values.

The recent years have witnessed rapid strides in the use of cloud computing and its countless applications. A cloud can contain massive volumes of multimedia data in the form of images, video and audio. Cloud computing platforms confront challenges in terms of data confidentiality, message integrity, user authentication and compression. Multimedia data needs plenty of storage capacity. Consequently, there is a need for multimedia data compression to reduce data size. Compression techniques are quite reliable, offering benefits to organizations dealing with metasized data in the cloud. Compressing large quanta of data leads to superior utilization of cloud storage. Compression techniques can compress data used for storage and transmission, yet compression alone is inadequate because multimedia data shared should, of necessity, be secure. Therefore, both multimedia compression and security are mandatory in the cloud. The chief goal of this paper is to propose a new framework, comprising multiscale transforms, public key cryptography and appropriate encoding techniques, that performs joint medical image compression and image encryption in the cloud. Multiscale transforms play a lead role in image compression, and the ones discussed in this paper include wavelet, bandelet, curvelet, ridgelet and contourlet transforms. Wavelet transforms offer robust localization both in terms of time and frequency domains. Bandelet transforms offer natural images geometric regularity to help improve the efficiency of representation. Curvelet transforms handle curve discontinuities well, with ridgelet transforms being the core idea behind curvelets. Contourlet transforms capture smooth contours and edges at any orientation. The Rivest-Shamir-Adleman (RSA) algorithm is used to encrypt images to provide maximum security when they are being transferred. Encoding techniques involved in this paper comprise the Embedded Zerotree Wavelet (EZW), Set Partitioning in Hierarchical Trees (SPIHT), Wavelet Difference Reduction (WDR), and Adaptively Scanned Wavelet Difference Reduction (ASWDR). Performance parameters such as peak signal to noise ratio (PSNR), mean square error (MSE), image quality index and structural similarity index (SSIM) are used for evaluation. It is justified that the proposed framework compresses images securely in the cloud.

Multiple sequence alignment (MSA) data play a crucial role in the study of protein mutations, with contact prediction being a notable application. Existing methods are often model-based or algorithmic and typically do not incorporate statistical inference to quantify the uncertainty of the prediction outcomes. To address this, we propose a novel framework that transforms the task of contact prediction into a statistical testing problem. Our approach is motivated by the partial correlation for continuous random variables. With one-hot encoding of MSA data, we are able to construct a partial correlation graph for multivariate categorical variables. In this framework, two connected nodes in the graph indicate that the corresponding positions on the protein form a contact. A new spectrum-based test statistic is introduced to test whether two positions are partially correlated. Moreover, the new framework enables the identification of amino acid combinations that contribute to the correlation within the identified contacts, an important but largely unexplored aspect of protein mutations. Numerical experiments demonstrate that our proposed method is valid in terms of controlling Type I errors and powerful in general. Real data applications on various protein families further validate the practical utility of our approach in coevolution and mutation analysis.