The deferred path heuristic for the generalized tree alignment problem

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.

Co-evolution has an important function in the evolution of species and it is clearly manifested in certain scenarios such as host–parasite and predator–prey interactions, symbiosis and mutualism. The extrapolation of the concepts and methodologies developed for the study of species co-evolution at the molecular level has prompted the development of a variety of computational methods able to predict protein interactions through the characteristics of co-evolution. Particularly successful have been those methods that predict interactions at the genomic level based on the detection of pairs of protein families with similar evolutionary histories (similarity of phylogenetic trees: mirrortree). Future advances in this field will require a better understanding of the molecular basis of the co-evolution of protein families. Thus, it will be important to decipher the molecular mechanisms underlying the similarity observed in phylogenetic trees of interacting proteins, distinguishing direct specific molecular interactions from other general functional constraints. In particular, it will be important to separate the effects of physical interactions within protein complexes (‘co-adaptation') from other forces that, in a less specific way, can also create general patterns of co-evolution.

The following problems are worth studying: Open problems on the Steiner ratio, such as Chung-Gilbert’s conjecture, Graham-Hwang’s conjecture, and Cielick’s conjecture, etc.. Find better approximation for network Steiner trees and establish an explicit lower bound for the approximation performance ratio of network Steiner trees. Close the gap between the lower bound and the upper bound for the approximation performance ratio of Steiner minimum arborescence. Find more efficient approximation algorithms for on-line and dynamic Steiner minimum trees and various Steiner tree packing problems. Find good approximation algorithms for multi-weighted Steiner trees and multiphase Steiner trees and study close relationship between multi-weighted Steiner trees, multiphase Steiner trees, and phylogenetic trees. Make clear whether there exists a polynomial-time approximation scheme for class Steiner tree in the special case with the real world background and highway interconnection problem. Close the gap between the lower bound and the upper bound for the approximation performance ratio of bottleneck Steiner tree in the Euclidean plane and make clear whether there exists a polynomial-time approximation scheme for the Steiner tree with minimum number of Steiner points and bounded edge-length. Implement efficient approximation algorithms to meet the requests from industries.

Accurate prediction of MHC-peptide binding affinity remains a challenge for immunotherapeutic development. Existing methods struggle to jointly model functional semantics of polymorphic residues, evolutionary conservation constraints, and structural dynamic. We propose the Contrast learning-based Multi-feature Heterogeneous Subgraph model (CMHS) with sequence and structural representation. For sequence representation, we introduce LoRA fine-tuning to obtain the MHC-exclusive sequence representation from ESM2, then jointly BLOSUM50 to capture long-range functional dependencies and evolutionarily conserved residues. For structural representation, we use the biophysics-guided heterogeneous graph network. Constructing an MHC-peptide graph with a novel trainable Gaussian noise layer guided by crystallographic B-factors to dynamically simulate electron density uncertainty, coupled with a three-stage message-passing framework with subgraph aggregation, subgraph extraction and heterogeneous. Finally, to align sequence and graph representation spaces, we use contrastive learning to obtain a more comprehensive representation and to enhance the ability of model prediction. Evaluations on 16 HLA allele benchmarks show average SRCC improvements of 8.7%, with improvements of average AUC of 7.6%. This work establishes a new paradigm for predicting hypervariable immune interactions. The corresponding code can be founded in github.

Highly accurate estimation of phylogenetic trees for large data sets is difficult, in part because multiple sequence alignments must be accurate for phylogeny estimation methods to be accurate. Coestimation of alignments and trees has been attempted but currently only SATé estimates reasonably accurate trees and alignments for large data sets in practical time frames (Liu K., Raghavan S., Nelesen S., Linder C.R., Warnow T. 2009b. Rapid and accurate large-scale coestimation of sequence alignments and phylogenetic trees. Science. 324:1561-1564). Here, we present a modification to the original SATé algorithm that improves upon SATé (which we now call SATé-I) in terms of speed and of phylogenetic and alignment accuracy. SATé-II uses a different divide-and-conquer strategy than SATé-I and so produces smaller more closely related subsets than SATé-I; as a result, SATé-II produces more accurate alignments and trees, can analyze larger data sets, and runs more efficiently than SATé-I. Generally, SATé is a metamethod that takes an existing multiple sequence alignment method as an input parameter and boosts the quality of that alignment method. SATé-II-boosted alignment methods are significantly more accurate than their unboosted versions, and trees based upon these improved alignments are more accurate than trees based upon the original alignments. Because SATé-I used maximum likelihood (ML) methods that treat gaps as missing data to estimate trees and because we found a correlation between the quality of tree/alignment pairs and ML scores, we explored the degree to which SATé's performance depends on using ML with gaps treated as missing data to determine the best tree/alignment pair. We present two lines of evidence that using ML with gaps treated as missing data to optimize the alignment and tree produces very poor results. First, we show that the optimization problem where a set of unaligned DNA sequences is given and the output is the tree and alignment of those sequences that maximize likelihood under the Jukes-Cantor model is uninformative in the worst possible sense. For all inputs, all trees optimize the likelihood score. Second, we show that a greedy heuristic that uses GTR+Gamma ML to optimize the alignment and the tree can produce very poor alignments and trees. Therefore, the excellent performance of SATé-II and SATé-I is not because ML is used as an optimization criterion for choosing the best tree/alignment pair but rather due to the particular divide-and-conquer realignment techniques employed.

Most multiple sequence alignment programs explicitly or implicity try to optimize some score associated with the resulting alignment. Although the sum-of-pairs score is currently most widely used, it is inappropriate when the phylogenetic relationships among the sequences to be aligned are not evenly distributed, since the contributions of densely populated groups dominate those of minor members. This paper proposes an iterative multiple sequence alignment method which optimizes a weighted sum-of-pairs score, in which the weights given to individual sequence pairs are adjusted to compensate for the biased contributions. A simple method that rapidly calculates such a set of weights for a given phylogenetic tree is presented. The multiple sequence alignment is refined through partitioning and realignment restricted to the edges of the tree. Under this restriction, profile-based fast and rigorous group-to-group alignment is achieved at each iteration, rendering the overall computational cost virtually identical to that using an unweighted score. Consistency of nearly 90% was attained between structural and sequence alignments of multiple divergent globins, confirming the effectiveness of this strategy in improving the quality of multiple sequence alignment.

Multiple protein sequence alignment using double-dynamic programming

Multiple protein sequence alignment using double-dynamic programming.

DOMO: a new database of aligned protein domains

BackgroundThe inference of homologies among DNA sequences, that is, positions in multiple genomes that share a common evolutionary origin, is a crucial, yet difficult task facing biologists. Its computational counterpart is known as the multiple sequence alignment problem. There are various criteria and methods available to perform multiple sequence alignments, and among these, the minimization of the overall cost of the alignment on a phylogenetic tree is known in combinatorial optimization as the Tree Alignment Problem. This problem typically occurs as a subproblem of the Generalized Tree Alignment Problem, which looks for the tree with the lowest alignment cost among all possible trees. This is equivalent to the Maximum Parsimony problem when the input sequences are not aligned, that is, when phylogeny and alignments are simultaneously inferred.ResultsFor large data sets, a popular heuristic is Direct Optimization (DO). DO provides a good tradeoff between speed, scalability, and competitive scores, and is implemented in the computer program POY. All other (competitive) algorithms have greater time complexities compared to DO. Here, we introduce and present experiments a new algorithm Affine-DO to accommodate the indel (alignment gap) models commonly used in phylogenetic analysis of molecular sequence data. Affine-DO has the same time complexity as DO, but is correctly suited for the affine gap edit distance. We demonstrate its performance with more than 330,000 experimental tests. These experiments show that the solutions of Affine-DO are close to the lower bound inferred from a linear programming solution. Moreover, iterating over a solution produced using Affine-DO shows little improvement.ConclusionsOur results show that Affine-DO is likely producing near-optimal solutions, with approximations within 10% for sequences with small divergence, and within 30% for random sequences, for which Affine-DO produced the worst solutions. The Affine-DO algorithm has the necessary scalability and optimality to be a significant improvement in the real-world phylogenetic analysis of sequence data.

BackgroundHigh-throughput experimental technologies are generating tremendous amounts of genomic data, offering valuable resources to answer important questions and extract biological insights. Storing this sheer amount of genomic data has become a major concern in bioinformatics. General purpose compression techniques (e.g. gzip, bzip2, 7-zip) are being widely used due to their pervasiveness and relatively good speed. However, they are not customized for genomic data and may fail to leverage special characteristics and redundancy of the biomolecular sequences.ResultsWe present a new lossless compression method CHAPAO (COmpressing Alignments using Hierarchical and Probabilistic Approach), which is especially designed for multiple sequence alignments (MSAs) of biomolecular data and offers very good compression gain. We have introduced a novel hierarchical referencing technique to represent biomolecular sequences which combines likelihood based analyses of the sequence similarities and graph theoretic algorithms. We performed an extensive evaluation study using a collection of real biological data from the avian phylogenomics project, 1000 plants project (1KP), and 16S and 23S rRNA datasets. We report the performance of CHAPAO in comparison with general purpose compression techniques as well as with MFCompress and Nucleotide Archival Format (NAF)—two of the best known methods especially designed for FASTA files. Experimental results suggest that CHAPAO offers significant improvements in compression gain over most other alternative methods. CHAPAO is freely available as an open source software at https://github.com/ashiq24/CHAPAO.ConclusionCHAPAO advances the state-of-the-art in compression algorithms and represents a potential alternative to the general purpose compression techniques as well as to the existing specialized compression techniques for biomolecular sequences.

Erwin Schrödinger's question "What is life?" received the answer for decades of "physics + chemistry". The concepts of Alain Turing and John von Neumann introduced a third term: "information". This led to the understanding of nucleic acid sequences as a natural code. Manfred Eigen adapted the concept of Hammings "sequence space". Similar to Hilbert space, in which every ontological entity could be defined by an unequivocal point in a mathematical axiomatic system, in the abstract "sequence space" concept each point represents a unique syntactic structure and the value of their separation represents their dissimilarity. In this concept molecular features of the genetic code evolve by means of self-organisation of matter. Biological selection determines the fittest types among varieties of replication errors of quasi-species. The quasi-species concept dominated evolution theory for many decades. In contrast to this, recent empirical data on the evolution of DNA and its forerunners, the RNA-world and viruses indicate cooperative agent-based interactions. Group behaviour of quasi-species consortia constitute de novo and arrange available genetic content for adaptational purposes within real-life contexts that determine epigenetic markings. This review focuses on some fundamental changes in biology, discarding its traditional status as a subdiscipline of physics and chemistry.

A new numerical approach for DNA representation using modified Gabor wavelet transform for the identification of protein coding regions

At the present, coding sequence (CDS) has been discovered and larger CDS is being revealed frequently. Approaches and related tools have also been developed and upgraded concurrently, especially for phylogenetic tree analysis. This paper proposes an integrated automatic Taverna workflow for the phylogenetic tree inferring analysis using public access web services at European Bioinformatics Institute (EMBL-EBI) and Swiss Institute of Bioinformatics (SIB), and our own deployed local web services. The workflow input is a set of CDS in the Fasta format. The workflow supports 1,000 to 20,000 numbers in bootstrapping replication. The workflow performs the tree inferring such as Parsimony (PARS), Distance Matrix - Neighbor Joining (DIST-NJ), and Maximum Likelihood (ML) algorithms of EMBOSS PHYLIPNEW package based on our proposed Multiple Sequence Alignment (MSA) similarity score. The local web services are implemented and deployed into two types using the Soaplab2 and Apache Axis2 deployment. There are SOAP and Java Web Service (JWS) providing WSDL endpoints to Taverna Workbench, a workflow manager. The workflow has been validated, the performance has been measured, and its results have been verified. Our workflow's execution time is less than ten minutes for inferring a tree with 10,000 replicates of the bootstrapping numbers. This paper proposes a new integrated automatic workflow which will be beneficial to the bioinformaticians with an intermediate level of knowledge and experiences. All local services have been deployed at our portal http://bioservices.sci.psu.ac.th.

Multiple Sequence Alignment (MSA) is an important process in the analysis of biological sequences by making comparisons of several biological sequences. In some MSA algorithms (such as CLUSTALW, for example), the formation of phylogenetic trees as a guideline in the alignment process has an important role in determining the accuracy of the final alignment results. From the whole MSA process, the formation of phylogenetic tree computational time increased as the number of sequences increases. Computing the similarity score for all sequence pairs takes a lot of time, causing a long computation time problem. In addition, this research uses the neighbor join method as a technique to build a phyloghenetic tree This Research examines the potential efficiency of computational phylogenetic trees in parallel and is distributed to the Hadoop environment using MapReduce. The results showed that a phylogenetic tree can be generated using MapReduce computation and results in 19%-time efficiency from 2 and 3 computation nodes.