Alignment-free Sequence Comparison Methods Research Articles

Numerical Characterization of DNA Sequences for Alignment-free Sequence Comparison - A Review.

Biological macromolecules, namely, DNA, RNA, and protein, have their building blocks organized in a particular sequence and the sequential arrangement encodes the evolutionary history of the organism (species). Hence, biological sequences have been used for studying evolutionary relationships among the species. This is usually carried out by Multiple Sequence Algorithms (MSA). Due to certain limitations of MSA, alignment-free sequence comparison methods were developed. The present review is on alignment-free sequence comparison methods carried out using the numerical characterization of DNA sequences. The graphical representation of DNA sequences by chaos game representation and other 2-dimensional and 3-dimensional methods are discussed. The evolution of numerical characterization from the various graphical representations and the application of the DNA invariants thus computed in phylogenetic analysis are presented. The extension of computing molecular descriptors in chemometrics to the calculation of a new set of DNA invariants and their use in alignment-free sequence comparison in an N-dimensional space and construction of phylogenetic trees are also reviewed. The phylogenetic tress constructed by the alignment-free sequence comparison methods using DNA invariants were found to be better than those constructed using alignment-based tools such as PHLYIP and ClustalW. One of the graphical representation methods is now extended to study viral sequences of infectious diseases for the identification of conserved regions to design peptidebased vaccines by combining numerical characterization and graphical representation.

Alignment free sequence comparison methods and reservoir host prediction.

MotivationThe emergence and subsequent pandemic of the SARS-CoV-2 virus raised urgent questions about its origin and, particularly, its reservoir host. These types of questions are long-standing problems in the management of emerging infectious diseases and are linked to virus discovery programs and the prediction of viruses that are likely to become zoonotic. Conventional means to identify reservoir hosts have relied on surveillance, experimental studies and phylogenetics. More recently, machine learning approaches have been applied to generate tools to swiftly predict reservoir hosts from sequence data.ResultsHere, we extend a recent work that combined sequence alignment and a mixture of alignment-free approaches using a gradient boosting machines (GBMs) machine learning model, which integrates genomic traits (GT) and phylogenetic neighbourhood (PN) signatures to predict reservoir hosts. We add a more uniform approach by applying Machine Learning with Digital Signal Processing (MLDSP)-based structural patterns (M-SP). The extended model was applied to an existing virus/reservoir host dataset and to the SARS-CoV-2 and related viruses and generated an improvement in prediction accuracy.Availability and implementationThe source code used in this work is freely available at https://github.com/bill1167/hostgbms.Supplementary informationSupplementary data are available at Bioinformatics online.

A new graph-theoretic approach to determine the similarity of genome sequences based on nucleotide triplets

Methods of finding sequence similarity play a significant role in computational biology. Owing to the rapid increase of genome sequences in public databases, the evolutionary relationship of species becomes more challenging. But traditional alignment-based methods are found inappropriate due to their time-consuming nature. Therefore, it is necessary to find a faster method, which applies to species phylogeny. In this paper, a new graph-theory based alignment-free sequence comparison method is proposed. A complete-bipartite graph is used to represent each genome sequence based on its nucleotide triplets. Subsequently, with the help of the weights of edges of the graph, a vector descriptor is formed. Finally, the phylogenetic tree is drawn using the UPGMA algorithm. In the present case, the datasets for comparison are related to mammals, viruses, and bacteria. In most of the cases, the phylogeny in the present case is found to be more satisfactory as compared to earlier methods.

Benchmarking of alignment-free sequence comparison methods

BackgroundAlignment-free (AF) sequence comparison is attracting persistent interest driven by data-intensive applications. Hence, many AF procedures have been proposed in recent years, but a lack of a clearly defined benchmarking consensus hampers their performance assessment.ResultsHere, we present a community resource (http://afproject.org) to establish standards for comparing alignment-free approaches across different areas of sequence-based research. We characterize 74 AF methods available in 24 software tools for five research applications, namely, protein sequence classification, gene tree inference, regulatory element detection, genome-based phylogenetic inference, and reconstruction of species trees under horizontal gene transfer and recombination events.ConclusionThe interactive web service allows researchers to explore the performance of alignment-free tools relevant to their data types and analytical goals. It also allows method developers to assess their own algorithms and compare them with current state-of-the-art tools, accelerating the development of new, more accurate AF solutions.

Genome classification improvements based on k-mer intervals in sequences

Given the vast amount of genomic data, alignment-free sequence comparison methods are required due to their low computational complexity. k-mer based methods can improve comparison accuracy by extracting an effective feature of the genome sequences. The aim of this paper is to extract k-mer intervals of a sequence as a feature of a genome for high comparison accuracy. In the proposed method, we calculated the distance between genome sequences by comparing the distribution of k-mer intervals. Then, we identified the classification results using phylogenetic trees. We used viral, mitochondrial (MT), microbial and mammalian genome sequences to perform classification for various genome sets. We confirmed that the proposed method provides a better classification result than other k-mer based methods. Furthermore, the proposed method could efficiently be applied to long sequences such as human and mouse genomes.

Alignment-free Sequence Searching over Whole Genomes Using 3D random plot of Query DNA Sequences

Most genomic data studies are based on sequence comparisons and searches, and comparison models based on alignment algorithms are most commonly used. This method is very accurate, but it is useful when the query is short in kilobytes, because it requires the quadratic time and space complexity, O(n2) where n is the length of target and query sequences. With the development of Next Generation Sequencing techniques, researches on whole genome sequence data of megabyte size are being actively studied, and new comparison and search methods for large-scale sequence data are needed. We propose a new alignment-free sequence comparison and search method to overcome the limitations of the alignment-based model. In this graphical model, the sequence searching problem in DNA strings can be reduced to find some parts of geometric object within a relatively small-scale geometric space. When comparing similarity by modifying sequences of similar length, we can confirm that the comparison model is appropriate by accurately reflecting the degree of similarity. When searching the query sequence comparison model based on 200MB sized whole genome sequence, using the compressed coordinate information, it was able to search the 10MB sequences in 22s, which is a very reduced time compared to alignment. Although it is not possible to find the exact position of the base pair unit as in the alignment result, it is a model that can be used as a preprocessing process to quickly search a whole genome sequence of several hundred megabytes-size.

K2 and K2*: efficient alignment-free sequence similarity measurement based on Kendall statistics.

Alignment-free sequence comparison methods can compute the pairwise similarity between a huge number of sequences much faster than sequence-alignment based methods. We propose a new non-parametric alignment-free sequence comparison method, called K2, based on the Kendall statistics. Comparing to the other state-of-the-art alignment-free comparison methods, K2 demonstrates competitive performance in generating the phylogenetic tree, in evaluating functionally related regulatory sequences, and in computing the edit distance (similarity/dissimilarity) between sequences. Furthermore, the K2 approach is much faster than the other methods. An improved method, K2*, is also proposed, which is able to determine the appropriate algorithmic parameter (length) automatically, without first considering different values. Comparative analysis with the state-of-the-art alignment-free sequence similarity methods demonstrates the superiority of the proposed approaches, especially with increasing sequence length, or increasing dataset sizes. The K2 and K2* approaches are implemented in the R language as a package and is freely available for open access (http://community.wvu.edu/daadjeroh/projects/K2/K2_1.0.tar.gz). yueljiang@163.com. Supplementary data are available at Bioinformatics online.

Msktuple: An integrated R library for alignment-free multiple sequence k-tuple analysis

Recently alignment-free sequence comparison methods based on promoter-frequency distance measures have gained popularity. This paper reports on the implementation and validation of several alignment-free sequence analysis methods for representing and quantifying between-sequence distances and sequence variability. The msktuple library includes the following sequence comparison techniques: locational k-tuple, naive k-tuple, CV-Tree, and their ensemble variants. These metrics are used to determine the dissimilarity between sequences using k-letter words. In support of open-science, we provide open-source software, R-scripts, and protocols implementing the new techniques. These tools will support collaboration, enable independent validation, promote result reproducibility and enable tool interoperability.

A Provably Efficient Algorithm for the k-Mismatch Average Common Substring Problem.

Alignment-free sequence comparison methods are attracting persistent interest, driven by data-intensive applications in genome-wide molecular taxonomy and phylogenetic reconstruction. Among all the methods based on substring composition, the average common substring (ACS) measure admits a straightforward linear time sequence comparison algorithm, while yielding impressive results in multiple applications. An important direction of this research is to extend the approach to permit a bounded edit/hamming distance between substrings, so as to reflect more accurately the evolutionary process. To date, however, algorithms designed to incorporate k ≥ 1 mismatches have O(n(2)) worst-case time complexity, where n is the total length of the input sequences. On the other hand, accounting for mismatches has shown to lead to much improved classification, while heuristics can improve practical performance. In this article, we close the gap by presenting the first provably efficient algorithm for the k-mismatch average common string (ACSk) problem that takes O(n) space and O(n log(k) n) time in the worst case for any constant k. Our method extends the generalized suffix tree model to incorporate a carefully selected bounded set of perturbed suffixes, and can be applied to other complex approximate sequence matching problems.

Spaced words and kmacs: fast alignment-free sequence comparison based on inexact word matches.

In this article, we present a user-friendly web interface for two alignment-free sequence-comparison methods that we recently developed. Most alignment-free methods rely on exact word matches to estimate pairwise similarities or distances between the input sequences. By contrast, our new algorithms are based on inexact word matches. The first of these approaches uses the relative frequencies of so-called spaced words in the input sequences, i.e. words containing ‘don't care’ or ‘wildcard’ symbols at certain pre-defined positions. Various distance measures can then be defined on sequences based on their different spaced-word composition. Our second approach defines the distance between two sequences by estimating for each position in the first sequence the length of the longest substring at this position that also occurs in the second sequence with up to k mismatches. Both approaches take a set of deoxyribonucleic acid (DNA) or protein sequences as input and return a matrix of pairwise distance values that can be used as a starting point for clustering algorithms or distance-based phylogeny reconstruction. The two alignment-free programmes are accessible through a web interface at ‘Göttingen Bioinformatics Compute Server (GOBICS)’: http://spaced.gobics.de http://kmacs.gobics.de and the source codes can be downloaded.

Information entropy based methods for genome comparison

A plethora of biologically useful information lies obscured in the genomes of organisms. Encoded within the genome of an organism is the information about its evolutionary history. Evolutionary signals are scattered throughout the genome. Bioinformatics approaches are frequently invoked to deconstruct the evolutionary patterns underlying genomes, which are difficult to decipher using traditional laboratory experiments. However, interpreting constantly evolving genomes is a non-trivial task for bioinformaticians. Processes such as mutations, recombinations, insertions and deletions make genomes not only heterogeneous and difficult to decipher but also renders direct sequence comparison less effective. Here we present a brief overview of the sequence comparison methods with a focus on recently proposed alignment-free sequence comparison methods based on Shannon information entropy. Many of these sequence comparison methods have been adapted to construct phylogenetic trees to infer relationships among organisms.

Normalized Feature Vectors: A Novel Alignment-Free Sequence Comparison Method Based on the Numbers of Adjacent Amino Acids

Based on all kinds of adjacent amino acids (AAA), we map each protein primary sequence into a 400 by ((L-1)) matrix (M). In addition, we further derive a normalized 400-tuple mathematical descriptors (D), which is extracted from the primary protein sequences via singular values decomposition (SVD) of the matrix. The obtained 400-D normalized feature vectors (NFVs) further facilitate our quantitative analysis of protein sequences. Using the normalized representation of the primary protein sequences, we analyze the similarity for different sequences upon two data sets: 1) ND5 sequences from nine species and 2) transferrin sequences of 24 vertebrates. We also compared the results in this study with those from other related works. These two experiments illustrate that our proposed NFV-AAA approach does perform well in the field of similarity analysis of sequence.

Protein map: An alignment-free sequence comparison method based on various properties of amino acids

In this paper, we propose a new protein map which incorporates with various properties of amino acids. As a powerful tool for protein classification, this new protein map both considers phylogenetic factors arising from amino acid mutations and provides computational efficiency for the huge amount of data. The ten amino acid physico-chemical properties (the chemical composition of the side chain, two polarity measures, hydropathy, isoelectric point, volume, aromaticity, aliphaticity, hydrogenation, and hydroxythiolation) are utilized according to their relative importance. Moreover, during the course of calculation of genetic distances between pairs of proteins, this approach does not require any alignment of sequences. Therefore, the proposed model is easier and quicker in handling protein sequences than multiple alignment methods, and gives protein classification greater evolutionary significance at the amino acid sequence level.

Extension of molecular similarity analysis approach to classification of DNA sequences using DNA descriptors

Several alignment-free sequence comparison methods are available which use similarity, based on a particular numerical descriptor of biological sequences. Any loss of information incurred in the transformation of a sequence into a numerical descriptor affects the results. A pool of descriptors that use different algorithms in their computation is expected to suffer minimum loss of information and an attempt is made in this direction to study the similarity of DNA sequences. A number of descriptors based on information theory and connectivity were computed for DNA sequences. Principal component analysis (PCA) was used to extract minimum number (N) of orthogonal descriptors, principal components (PCs). Similarity/dissimilarity clustering of DNA sequences were carried out in the N-dimensional similarity space constructed using the PCs extracted from the DNA descriptors. The paper explains the extension of quantitative molecular similarity analysis (QMSA) from the prediction of physicochemical properties and toxicity of chemicals to bioinformatics for the classification of DNA sequences.

Alignment-Free Sequence Comparison Using N-Dimensional Similarity Space

Several alignment free sequence comparison methods are available and they use similarity, based on a particular numerical descriptor of biological sequences. Any loss of information incurred in the transformation of a sequence into a numerical descriptor affects the results. A pool of descriptors that use different algorithms in their computation is expected to suffer minimum loss of information and an attempt is made in this direction to study the similarity of DNA sequences that are homogenous or heterogeneous. Several numerical descriptors for the characterization of DNA sequences are described, based on information theoretic approach, connectivity of vertex weighted line-graphs and those derived from the matrices obtained from the graphs constructed by depicting DNA sequences as a random walk on a Euclidean plane. The information theoretic descriptors were obtained based on the L-tuple approach for the combination of different numbers of bases. The connectivity type descriptors were calculated by converting the DNA sequence into vertex weighted graphs in which vertices (nucleotide) were assigned weights based on the pKa of the bases. The graphical representations were converted into numerical descriptors by constructing matrices. Computer programs were developed to calculate seventy DNA descriptors; 560 sequences of different types of organisms were used. After initial data analysis to eliminate almost perfectly correlated descriptors, orthogonal descriptors were obtained by performing principal component analysis. Principal components (PCs) were used to construct an N-dimensional similarity space wherein the 560 sequences were clustered by k-means cluster algorithm. Five principal components (orthogonal descriptors) were extracted and found to explain 92% of data variance. The PCs were used to cluster the sequences in a five-dimensional similarity space. The similarity-based dissimilarity clustering procedure using numerical descriptors was found to be effective for studying similarity/ dissimilarity of large number of sequences.

Statistical considerations underpinning an alignment-free sequence comparison method

The D 2 statistic is defined as the number of word matches of prespecified length k , with up to t mismatches, shared between two given sequences. This statistic finds its application in alignment-free comparisons of biological sequences. It has two main advantages over alignment-based methods for nucleotide and amino-acid sequence comparisons, such as BLAST (basic local alignment search tool). These are (i) D 2 does not assume that homologous segments are contiguous, and (ii) the algorithm is computationally extremely fast, the runtime being proportional to the size of the sequences in the case of exact matches. This review article summarises results to date on determining the distributional properties of the D 2 statistic for a range of biologically relevant parameters, describes existing applications of the method, and outlines future research directions.

Empirical distribution of k-word matches in biological sequences

This study focuses on an alignment-free sequence comparison method: the number of words of length k shared between two sequences, also known as the D 2 statistic. The advantages of the use of this statistic over alignment-based methods are firstly that it does not assume that homologous segments are contiguous, and secondly that the algorithm is computationally extremely fast, the runtime being proportional to the size of the sequence under scrutiny. Existing applications of the D 2 statistic include the clustering of related sequences in large EST databases such as the STACK database. Such applications have typically relied on heuristics without any statistical basis. Rigorous statistical characterisations of the distribution of D 2 have subsequently been undertaken, but have focussed on the distribution's asymptotic behaviour, leaving the distribution of D 2 uncharacterised for most practical cases. The work presented here bridges these two worlds to give usable approximations of the distribution of D 2 for ranges of parameters most frequently encountered in the study of biological sequences.