A platform for biological sequence comparison on parallel computers

We have written two programs for searching biological sequencedatabases that run on Intel hypercube computers. PSCANLJB comparesa single sequence against a sequence library, and PCOMPLIB comparesall the entries in one sequence library against a second library.The programs provide a general framework for similarity searching;they include functions for reading in query sequences, searchparameters and library entries, and reporting the results ofa search. We have isolated the code for the specific functionthat calculates the similarity score between the query and librarysequence; alternative searching algorithms can be implementedby editing two files. We have implemented the rapid FASTA sequencecomparison algorithm and the more rigorous Smith — Watermanalgorithm within this framework. The PSCANLIB program on a 16node iPSC/2 80386-based hypercube can compare a 229 amino acidprotein sequence with a 3.4 million residue sequence libraryin {small tilde}16s with the FASTA algorithm. Using the Smith— Waterman algorithm, the same search takes 35 min. ThePCOMPUB program can compare a 0.8 millon amino acid proteinsequence library with itself in 5.3 min with FASTA on a third-generation32 node Intel iPSC/860 hypercube. Received on September 8, 1990; accepted on December 15, 1990     

Aligning two sequences within a specified diagonal band

We describe an algorithm for aligning two sequences within adiagonal band that requires only O(NW) computation time andO(N) space, where N is the length of the shorter of the twosequences and W is the width of the band. The basic algorithmcan be used to calculate either local or global alignment scores.Local alignments are produced by finding the beginning and endof a best local alignment in the band, and then applying theglobal alignment algorithm between those points. This algorithmhas been incorporated into the FASTA program package, whereit has decreased the amount of memory required to calculatelocal alignments from O(NW) to O(N) and decreased the time requiredto calculate optimized scores for every sequence in a proteinsequence database by 40%. On computers with limited memory,such as the IBM-PC, this improvement both allows longer sequencesto be aligned and allows optimization within wider bands, whichcan include longer gaps.     

Parallel Clustering Algorithm for Large Data Sets with Applications in Bioinformatics

Large sets of bioinformatical data provide a challenge in time consumption while solving the cluster identification problem, and that is why a parallel algorithm is so needed for identifying dense clusters in a noisy background. Our algorithm works on a graph representation of the data set to be analyzed. It identifies clusters through the identification of densely intraconnected subgraphs. We have employed a minimum spanning tree (MST) representation of the graph and solve the cluster identification problem using this representation. The computational bottleneck of our algorithm is the construction of an MST of a graph, for which a parallel algorithm is employed. Our high-level strategy for the parallel MST construction algorithm is to first partition the graph, then construct MSTs for the partitioned subgraphs and auxiliary bipartite graphs based on the subgraphs, and finally merge these MSTs to derive an MST of the original graph. The computational results indicate that when running on 150 CPUs, our algorithm can solve a cluster identification problem on a data set with 1,000,000 data points almost 100 times faster than on single CPU, indicating that this program is capable of handling very large data clustering problems in an efficient manner. We have implemented the clustering algorithm as the software CLUMP.     

Implementing noncollective parallel I/O in cluster environments using Active Message communication

A costeffective secondary storage architecture for parallel computers is to distribute storage across all processors, which then engage in either computation or I/O, depending on the demands of the moment. A difficulty associated with this architecture is that access to storage on another processor typically requires the cooperation of that processor, which can be hard to arrange if the processor is engaged in other computation. One partial solution to this problem is to require that remote I/O operations occur only via collective calls. In this paper, we describe an alternative approach based on the use of singlesided communication operations such as Active Messages. We present an implementation of this basic approach called Distant I/O and present experimental results that quantify the lowlevel performance of DIO mechanisms. This technique is exploited to support noncollective parallel shared file model for a large outofcore scientific application with very high I/O bandwidth requirements. The achieved performance exceeds by a wide margin the performance of a well equipped PIOFS parallel filesystem on the IBM SP.     

Searching protein sequence libraries: comparison of the sensitivity and selectivity of the Smith-Waterman and FASTA algorithms.

The sensitivity and selectivity of the FASTA and the Smith-Waterman protein sequence comparison algorithms were evaluated using the superfamily classification provided in the National Biomedical Research Foundation/Protein Identification Resource (PIR) protein sequence database. Sequences from each of the 34 superfamilies in the PIR database with 20 or more members were compared against the protein sequence database. The similarity scores of the related and unrelated sequences were determined using either the FASTA program or the Smith-Waterman local similarity algorithm. These two sets of similarity scores were used to evaluate the ability of the two comparison algorithms to identify distantly related protein sequences. The FASTA program using the ktup = 2 sensitivity setting performed as well as the Smith-Waterman algorithm for 19 of the 34 superfamilies. Increasing the sensitivity by setting ktup = 1 allowed FASTA to perform as well as Smith-Waterman on an additional 7 superfamilies. The rigorous Smith-Waterman method performed better than FASTA with ktup = 1 on 8 superfamilies, including the globins, immunoglobulin variable regions, calmodulins, and plastocyanins. Several strategies for improving the sensitivity of FASTA were examined. The greatest improvement in sensitivity was achieved by optimizing a band around the best initial region found for every library sequence. For every superfamily except the globins and immunoglobulin variable regions, this strategy was as sensitive as a full Smith-Waterman. For some sequences, additional sensitivity was achieved by including conserved but nonidentical residues in the lookup table used to identify the initial region.     

Filtering redundancies for sequence similarity search programs

Database scanning programs such as BLAST and FASTA are used nowadays by most biologists for the post-genomic processing of DNA or protein sequence information (in particular to retrieve the structure/function of uncharacterized proteins). Unfortunately, their results can be polluted by identical alignments (called redundancies) coming from the same protein or DNA sequences present in different entries of the database. This makes the efficient use of the listed alignments difficult. Pretreatment of databases has been proposed to suppress strictly identical entries. However, there still remain many identical alignments since redundancies may occur locally for entries corresponding to various fragments of the same sequence or for entries corresponding to very homologous sequences but differing at the level of a few residues such as ortholog proteins. In the present work, we show that redundant alignments can be indeed numerous even when working with a pretreated non-redundant data bank, going as high as 60% of the output results according to the query and the bank. Therefore the accuracy and the efficiency of the post-genomic work will be greatly increased if these redundancies are removed. To solve this up to now unaddressed problem, we have developed an algorithm that allows for the efficient and safe suppression of all the redundancies with no loss of information. This algorithm is based on various filtering steps that we describe here in the context of the Automat similarity search program, and such an algorithm should also be added to the other similarity search programs (BLAST, FASTA, etc...).     

Cost-intelligent application-specific data layout optimization for parallel file systems

Parallel file systems have been developed in recent years to ease the I/O bottleneck of high-end computing system. These advanced file systems offer several data layout strategies in order to meet the performance goals of specific I/O workloads. However, while a layout policy may perform well on some I/O workload, it may not perform as well for another. Peak I/O performance is rarely achieved due to the complex data access patterns. Data access is application dependent. In this study, a cost-intelligent data access strategy based on the application-specific optimization principle is proposed. This strategy improves the I/O performance of parallel file systems. We first present examples to illustrate the difference of performance under different data layouts. By developing a cost model which estimates the completion time of data accesses in various data layouts, the layout can better match the application. Static layout optimization can be used for applications with dominant data access patterns, and dynamic layout selection with hybrid replications can be used for applications with complex I/O patterns. Theoretical analysis and experimental testing have been conducted to verify the proposed cost-intelligent layout approach. Analytical and experimental results show that the proposed cost model is effective and the application-specific data layout approach can provide up to a 74% performance improvement for data-intensive applications.     

Micro flow bio-molecular computation

In this paper we provide a model for micro-flow based bio-molecular computation (MF-BMC). It provides an abstraction for the design of algorithms which account for the constraints of the model. Our MF-BMC model uses abstractions of both the recombinant DNA (RDNA) technology as well as of the micro-flow technology and takes into account both of their limitations. For example, when considering the efficiency of the recombinant DNA operation of annealing, we take into account the limitation imposed by the concentration of the reactants. The fabrication technology used to construct MEMS is limited to constructing relatively thin 3D structures. We abstract this by limiting the model to a small constant number of layers (as is done with VLSI models). Besides our contribution of the MF-BMC model, the paper contains two other classes of results. The main result is the volume and time efficient algorithm for message routing in the MF-BMC model, specifically useful for PA-Match. We will show that routing of strands between chambers will occur in time O(N x D/ m x n), where N is the number of strands in the MF-BMC, n is the number of chambers where RDNA operations are occurring, D is the diameter of the topology of the layout of the chambers, and m is proportional to the channel width. Operations that need annealing, such as PA-Match, are shown feasible in O(N2logN/n/n) volume instead of the previous use of omega(N2) volume, with reasonable time constraints. Applications of the volume efficient algorithm include the use of the Join operation for databases, logarithmic depth solutions to SAT (Boolean formula satisfiability) problems and parallel algorithms that execute on a PRAM. Existent algorithms can be mapped to ones that work efficiently in the MF-BMC model, whereas previous methods for applications such as PRAM simulation in BMC were not both time and volume efficient. Our other class of results are theoretical lower bounds on the quantities of DNA and the time needed to solve a problem in the MF-BMC model, analogous to lower bounds in VLSI. We bound the product BT from below, and further show that BT2 has a stronger lower bound of I2. Here B is the maximum amount of information encoded in the MF-BMC system at a time. T is the time for an algorithm to complete, and I is the information content of a problem.     

Modular implementation of dynamic algorithm switching in parallel simulations

We present a modular approach to implementing dynamic algorithm switching for parallel scientific software. By using a compositional framework based on function call interception techniques, our proposed method transparently integrates algorithm switching code with a given program without directly modifying the original code structure. Through fine-grained control of algorithmic behavior of an application at the level of functions, our approach supports design and implementation of application-specific switching scenarios in a modular way. Our approach encourages algorithm switching to dynamically perform at the loop end of a parallel simulation, where cooperating processes in concurrent execution typically synchronize and intermediate computation results are consistent. In this way, newly added switching operations do not cause race conditions that may produce unreliable computation results in parallel simulations. By applying our method to a real-world scientific application and adapting its algorithmic behavior to the properties of input problems, we demonstrate the applicability and effectiveness of our approach to constructing efficient parallel simulations.     

Super pairwise alignment (SPA): an efficient approach to global alignment for homologous sequences.

Sequence analysis is the basis of bioinformatics, while sequence alignment is a fundamental task for sequence analysis. The widely used alignment algorithm, Dynamic Programming, though generating optimal alignment, takes too much time due to its high computation complexity O(N(2)). In order to reduce computation complexity without sacrificing too much accuracy, we have developed a new approach to align two homologous sequences. The new approach presented here, adopting our novel algorithm which combines the methods of probabilistic and combinatorial analysis, reduces the computation complexity to as low as O(N). The computation speed by our program is at least 15 times faster than traditional pairwise alignment algorithms without a loss of much accuracy. We hence named the algorithm Super Pairwise Alignment (SPA). The pairwise alignment execution program based on SPA and the detailed results of the aligned sequences discussed in this article are available upon request.     

Efficient substructure RMSD query algorithms.

Protein structure analysis is a very important research topic in the molecular biology of the post-genomic era. The root mean square deviation (RMSD) is the most frequently used measure for comparing two protein three-dimensional (3-D) structures. In this paper, we deal with two fundamental problems related to the RMSD. We first deal with a problem called the "range RMSD query" problem. Given an aligned pair of structures, the problem is to compute the RMSD between two aligned substructures of them without gaps. This problem has many applications in protein structure analysis. We propose a linear-time preprocessing algorithm that enables constant-time RMSD computation. Next, we consider a problem called the "substructure RMSD query" problem, which is a generalization of the above range RMSD query problem. It is a problem to compute the RMSD between any substructures of two unaligned structures without gaps. Based on the algorithm for the range RMSD problem, we propose an O(nm) preprocessing algorithm that enables constant-time RMSD computation, where n and m are the lengths of the given structures. Moreover, we propose O(nm log r/r)-time and O(nm/r)-space preprocessing algorithm that enables O(r) query, where r is an arbitrary integer such that 1 < or = r < or = min(n, m). We also show that our strategy also works for another measure called the unit-vector root mean square deviation (URMSD), which is a variant of the RMSD.     

BioParser

The widely used programs BLAST (in this article, 'BLAST' includes both the National Center for Biotechnology Information [NCBI] BLAST and the Washington University version WU BLAST) and FASTA for similarity searches in nucleotide and protein databases usually result in copious output. However, when large query sets are used, human inspection rapidly becomes impractical. BioParser is a Perl program for parsing BLAST and FASTA reports. Making extensive use of the BioPerl toolkit, the program filters, stores and returns components of these reports in either ASCII or HTML format. BioParser is also capable of automatically feeding a local MySQL database with the parsed information, allowing subsequent filtering of hits and/or alignments with specific attributes. For this reason, BioParser is a valuable tool for large-scale similarity analyses by improving the access to the information present in BLAST or FASTA reports, facilitating extraction of useful information of large sets of sequence alignments, and allowing for easy handling and processing of the data. AVAILABILITY: BioParser is licensed under the Creative Commons Attribution-NonCommercial-NoDerivs 2.0 license terms (http://creativecommons.org/licenses/by-nc-nd/2.0/) and is available upon request. Additional information can be found at the BioParser website (http://www.dbbm.fiocruz.br/BioParser.html).     

Improving Data Access for Computational Grid Applications

High-performance computing increasingly occurs on “computational grids” composed of heterogeneous and geographically distributed systems of computers, networks, and storage devices that collectively act as a single “virtual” computer. A key challenge in this environment is to provide efficient access to data distributed across remote data servers. Our parallel I/O framework, called Armada, allows application and data-set providers to flexibly compose graphs of processing modules that describe the distribution, application interfaces, and processing required of the dataset before computation. Although the framework provides a simple programming model for the application programmer and the data-set provider, the resulting graph may contain bottlenecks that prevent efficient data access. In this paper, we present an algorithm used to restructure Armada graphs that distributes computation and data flow to improve performance in the context of a wide-area computational grid. This work was supported by Sandia National Laboratories under DOE contract DOE-AV6184. Ron A. Oldfield is a senior member of the technical staff at Sandia National Laboratories in Albuquerque, NM. He received the B.Sc. in computer science from the University of New Mexico in 1993. From 1993 to 1997, he worked in the computational sciences department of Sandia National Laboratories, where he specialized in seismic research and parallel I/O. He was the primary developer for the GONII-SSD (Gas and Oil National Information Infrastructure–Synthetic Seismic Dataset) project and a co-developer for the R&D 100 award winning project “Salvo”, a project to develop a 3D finite-difference prestack-depth migration algorithm for massively parallel architectures. From 1997 to 2003 he attended graduate school at Dartmouth college and received his Ph.D. in June, 2003. In September of 2003, he returned to Sandia to work in the Scalable Computing Systems department. His research interests include parallel and distributed computing, parallel I/O, and mobile computing. David Kotz is a Professor of Computer Science at Dartmouth College in Hanover NH. After receiving his A.B. in Computer Science and Physics from Dartmouth in 1986, he completed his Ph.D in Computer Science from Duke University in 1991. He returned to Dartmouth to join the faculty in 1991, where he is now Professor of Computer Science, Director of the Center for Mobile Computing, and Executive Director of the Institute for Security Technology Studies. His research interests include context-aware mobile computing, pervasive computing, wireless networks, and intrusion detection. He is a member of the ACM, IEEE Computer Society, and USENIX associations, and of Computer Professionals for Social Responsibility. For more information see http://www.cs.dartmouth.edu/dfk/.     

GMBlock: Optimizing data movement in a block-level storage sharing system over Myrinet

We present gmblock, a block-level storage sharing system over Myrinet which uses an optimized I/O path to transfer data directly between the storage medium and the network, bypassing the host CPU and main memory bus of the storage server. It is device driver independent and retains the protection and isolation features of the OS. We evaluate the performance of a prototype gmblock server and find that: (a) the proposed techniques eliminate memory and peripheral bus contention, increasing remote I/O bandwidth significantly, in the order of 20–200% compared to an RDMA-based approach, (b) the impact of remote I/O to local computation becomes negligible, (c) the performance characteristics of RAID storage combined with limited NIC resources reduce performance. We introduce synchronized send operations to improve the degree of disk to network I/O overlapping. We deploy the OCFS2 shared-disk filesystem over gmblock and show gains for various application benchmarks, provided I/O scheduling can eliminate the disk bottleneck due to concurrent access.     

一个新的核酸序列比对算法及其在序列全局比对中的应用

目前在序列比对中所广泛使用的动态规划算法,虽然能达到最优比对结果,但却由于具有高计算复杂度O(N_2)而极大地降低了计算效率。将多阶段动态规划决策算法用于两两序列比对并用Visual BASIC编程实现,结果发现该新算法在将计算复杂度减小到O(N)的同时,也能够获得较为理想的计算精度,预期将在序列全局比对中起重要作用。     

Information on the secondary structure improves the quality of protein sequence alignment

The most popular algorithms employed in the pairwise alignment of protein primary structures (Smith-Watermann (SW) algorithm, FASTA, BLAST, etc.) only analyze the amino acid sequence. The SW algorithm is the most accurate, yielding alignments that agree best with superimpositions of the corresponding spatial structures of proteins. However, even the SW algorithm fails to reproduce the spatial structure alignment when the sequence identity is lower than 30%. The objective of this work was to develop a new and more accurate algorithm taking the secondary structure of proteins into account. The alignments generated by this algorithm and having the maximal weight with the secondary structure considered proved to be more accurate than SW alignments. With sequences having less than 30% identity, the accuracy (i.e., the portion of reproduced positions of a reference alignment obtained by superimposing the protein spatial structures) of the new algorithm is 58 vs. 35% of the SW algorithm. The accuracy of the new algorithm is much the same with secondary structures established experimentally or predicted theoretically. Hence, the algorithm is applicable to proteins with unknown spatial structures. The program is available at ftp://194.149.64.196/STRUSWER/.     

BetaVoid: Molecular voids via beta‐complexes and Voronoi diagrams

Molecular external structure is important for molecular function, with voids on the surface and interior being one of the most important features. Hence, recognition of molecular voids and accurate computation of their geometrical properties, such as volume, area and topology, are crucial, yet most popular algorithms are based on the crude use of sampling points and thus are approximations even with a significant amount of computation. In this article, we propose an analytic approach to the problem using the Voronoi diagram of atoms and the beta‐complex. The correctness and efficiency of the proposed algorithm is mathematically proved and experimentally verified. The benchmark test clearly shows the superiority of BetaVoid to two popular programs: VOIDOO and CASTp. The proposed algorithm is implemented in the BetaVoid program which is freely available at the Voronoi Diagram Research Center ( http://voronoi.hanyang.ac.kr ). Proteins 2014; 82:1829–1849. © 2014 Wiley Periodicals, Inc.     

Optimizing reduced-space sequence analysis

MOTIVATION: Dynamic programming is the core algorithm of sequence comparison, alignment and linear hidden Markov model (HMM) training. For a pair of sequence lengths m and n, the problem can be solved readily in O(mn)time and O(mn)space. The checkpoint algorithm introduced by Grice et al. (CABIOS, 13, 45--53, 1997) runs in O(Lmn)time and O(Lm(L) square root of n)space, where L is a positive integer determined by m, n, and the amount of available workspace. The algorithm is appropriate for many string comparison problems, including all-paths and single-best-path hidden Markov model training, and is readily parallelizable. The checkpoint algorithm has a diagonal version that can solve the single-best-path alignment problem in O(mn)time and O(m + n)space. RESULTS: In this work, we improve performance by analyzing optimal checkpoint placement. The improved row checkpoint algorithm performs up to one half the computation of the original algorithm. The improved diagonal checkpoint algorithm performs up to 35% fewer computational steps than the original. We modified the SAM hidden Markov modeling package to use the improved row checkpoint algorithm. For a fixed sequence length, the new version is up to 33% faster for all-paths and 56% faster for single-best-path HMM training, depending on sequence length and allocated memory. Over a typical set of protein sequence lengths, the improvement is approximately 10%.     

Protein domain decomposition using a graph-theoretic approach

MOTIVATION: Automatic decomposition of a multi-domain protein into individual domains represents a highly interesting and unsolved problem. As the number of protein structures in PDB is growing at an exponential rate, there is clearly a need for more reliable and efficient methods for protein domain decomposition simply to keep the domain databases up-to-date. RESULTS: We present a new algorithm for solving the domain decomposition problem, using a graph-theoretic approach. We have formulated the problem as a network flow problem, in which each residue of a protein is represented as a node of the network and each residue--residue contact is represented as an edge with a particular capacity, depending on the type of the contact. A two-domain decomposition problem is solved by finding a bottleneck (or a minimum cut) of the network, which minimizes the total cross-edge capacity, using the classical Ford--Fulkerson algorithm. A multi-domain decomposition problem is solved through repeatedly solving a series of two-domain problems. The algorithm has been implemented as a computer program, called DomainParser. We have tested the program on a commonly used test set consisting of 55 proteins. The decomposition results are 78.2% in agreement with the literature on both the number of decomposed domains and the assignments of residues to each domain, which compares favorably to existing programs. On the subset of two-domain proteins (20 in number), the program assigned 96.7% of the residues correctly when we require that the number of decomposed domains is two.     

Fast,scalable generation of high‐quality protein multiple sequence alignments using Clustal Omega

Multiple sequence alignments are fundamental to many sequence analysis methods. Most alignments are computed using the progressive alignment heuristic. These methods are starting to become a bottleneck in some analysis pipelines when faced with data sets of the size of many thousands of sequences. Some methods allow computation of larger data sets while sacrificing quality, and others produce high‐quality alignments, but scale badly with the number of sequences. In this paper, we describe a new program called Clustal Omega, which can align virtually any number of protein sequences quickly and that delivers accurate alignments. The accuracy of the package on smaller test cases is similar to that of the high‐quality aligners. On larger data sets, Clustal Omega outperforms other packages in terms of execution time and quality. Clustal Omega also has powerful features for adding sequences to and exploiting information in existing alignments, making use of the vast amount of precomputed information in public databases like Pfam.