A benchmark of multiple sequence alignment programs upon structural RNAs.
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ABSTRACT:
SUBMITTER: Gardner PP
PROVIDER: S-EPMC1087786 | biostudies-literature | 2005
REPOSITORIES: biostudies-literature
Publications
A benchmark of multiple sequence alignment programs upon structural RNAs.
Gardner Paul P PP Wilm Andreas A Washietl Stefan S
Nucleic acids research 20050428 8
To date, few attempts have been made to benchmark the alignment algorithms upon nucleic acid sequences. Frequently, sophisticated PAM or BLOSUM like models are used to align proteins, yet equivalents are not considered for nucleic acids; instead, rather ad hoc models are generally favoured. Here, we systematically test the performance of existing alignment algorithms on structural RNAs. This work was aimed at achieving the following goals: (i) to determine conditions where it is appropriate to a ...[more]
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Project description:BackgroundThe performance of alignment programs is traditionally tested on sets of protein sequences, of which a reference alignment is known. Conclusions drawn from such protein benchmarks do not necessarily hold for the RNA alignment problem, as was demonstrated in the first RNA alignment benchmark published so far. For example, the twilight zone - the similarity range where alignment quality drops drastically - starts at 60 % for RNAs in comparison to 20 % for proteins. In this study we enhance the previous benchmark.ResultsThe RNA sequence sets in the benchmark database are taken from an increased number of RNA families to avoid unintended impact by using only a few families. The size of sets varies from 2 to 15 sequences to assess the influence of the number of sequences on program performance. Alignment quality is scored by two measures: one takes into account only nucleotide matches, the other measures structural conservation. The performance order of parameters--like nucleotide substitution matrices and gap-costs--as well as of programs is rated by rank tests.ConclusionMost sequence alignment programs perform equally well on RNA sequence sets with high sequence identity, that is with an average pairwise sequence identity (APSI) above 75 %. Parameters for gap-open and gap-extension have a large influence on alignment quality lower than APSI < or = 75 %; optimal parameter combinations are shown for several programs. The use of different 4 x 4 substitution matrices improved program performance only in some cases. The performance of iterative programs drastically increases with increasing sequence numbers and/or decreasing sequence identity, which makes them clearly superior to programs using a purely non-iterative, progressive approach. The best sequence alignment programs produce alignments of high quality down to APSI > 55 %; at lower APSI the use of sequence+structure alignment programs is recommended.
| S-EPMC1635699 | biostudies-literature
Project description:BackgroundMultiple sequence alignment (MSA) is an extremely useful tool for molecular and evolutionary biology and there are several programs and algorithms available for this purpose. Although previous studies have compared the alignment accuracy of different MSA programs, their computational time and memory usage have not been systematically evaluated. Given the unprecedented amount of data produced by next generation deep sequencing platforms, and increasing demand for large-scale data analysis, it is imperative to optimize the application of software. Therefore, a balance between alignment accuracy and computational cost has become a critical indicator of the most suitable MSA program. We compared both accuracy and cost of nine popular MSA programs, namely CLUSTALW, CLUSTAL OMEGA, DIALIGN-TX, MAFFT, MUSCLE, POA, Probalign, Probcons and T-Coffee, against the benchmark alignment dataset BAliBASE and discuss the relevance of some implementations embedded in each program's algorithm. Accuracy of alignment was calculated with the two standard scoring functions provided by BAliBASE, the sum-of-pairs and total-column scores, and computational costs were determined by collecting peak memory usage and time of execution.ResultsOur results indicate that mostly the consistency-based programs Probcons, T-Coffee, Probalign and MAFFT outperformed the other programs in accuracy. Whenever sequences with large N/C terminal extensions were present in the BAliBASE suite, Probalign, MAFFT and also CLUSTAL OMEGA outperformed Probcons and T-Coffee. The drawback of these programs is that they are more memory-greedy and slower than POA, CLUSTALW, DIALIGN-TX, and MUSCLE. CLUSTALW and MUSCLE were the fastest programs, being CLUSTALW the least RAM memory demanding program.ConclusionsBased on the results presented herein, all four programs Probcons, T-Coffee, Probalign and MAFFT are well recommended for better accuracy of multiple sequence alignments. T-Coffee and recent versions of MAFFT can deliver faster and reliable alignments, which are specially suited for larger datasets than those encountered in the BAliBASE suite, if multi-core computers are available. In fact, parallelization of alignments for multi-core computers should probably be addressed by more programs in a near future, which will certainly improve performance significantly.
| S-EPMC4015676 | biostudies-literature
Project description:BACKGROUND: Linear motifs (LMs) are abundant short regulatory sites used for modulating the functions of many eukaryotic proteins. They play important roles in post-translational modification, cell compartment targeting, docking sites for regulatory complex assembly and protein processing and cleavage. Methods for LM detection are now being developed that are strongly dependent on scores for motif conservation in homologous proteins. However, most LMs are found in natively disordered polypeptide segments that evolve rapidly, unhindered by structural constraints on the sequence. These regions of modular proteins are difficult to align using classical multiple sequence alignment programs that are specifically optimised to align the globular domains. As a consequence, poor motif alignment quality is hindering efforts to detect new LMs. RESULTS: We have developed a new benchmark, as part of the BAliBASE suite, designed to assess the ability of standard multiple alignment methods to detect and align LMs. The reference alignments are organised into different test sets representing real alignment problems and contain examples of experimentally verified functional motifs, extracted from the Eukaryotic Linear Motif (ELM) database. The benchmark has been used to evaluate and compare a number of multiple alignment programs. With distantly related proteins, the worst alignment program correctly aligns 48% of LMs compared to 73% for the best program. However, the performance of all the programs is adversely affected by the introduction of other sequences containing false positive motifs. The ranking of the alignment programs based on LM alignment quality is similar to that observed when considering full-length protein alignments, however little correlation was observed between LM and overall alignment quality for individual alignment test cases. CONCLUSION: We have shown that none of the programs currently available is capable of reliably aligning LMs in distantly related sequences and we have highlighted a number of specific problems. The results of the tests suggest possible ways to improve program accuracy for difficult, divergent sequences.
| S-EPMC2374782 | biostudies-literature
Project description:BACKGROUND: The alignment of two or more protein sequences provides a powerful guide in the prediction of the protein structure and in identifying key functional residues, however, the utility of any prediction is completely dependent on the accuracy of the alignment. In this paper we describe a suite of reference alignments derived from the comparison of protein three-dimensional structures together with evaluation measures and software that allow automatically generated alignments to be benchmarked. We test the OXBench benchmark suite on alignments generated by the AMPS multiple alignment method, then apply the suite to compare eight different multiple alignment algorithms. The benchmark shows the current state-of-the art for alignment accuracy and provides a baseline against which new alignment algorithms may be judged. RESULTS: The simple hierarchical multiple alignment algorithm, AMPS, performed as well as or better than more modern methods such as CLUSTALW once the PAM250 pair-score matrix was replaced by a BLOSUM series matrix. AMPS gave an accuracy in Structurally Conserved Regions (SCRs) of 89.9% over a set of 672 alignments. The T-COFFEE method on a data set of families with <8 sequences gave 91.4% accuracy, significantly better than CLUSTALW (88.9%) and all other methods considered here. The complete suite is available from http://www.compbio.dundee.ac.uk. CONCLUSIONS: The OXBench suite of reference alignments, evaluation software and results database provide a convenient method to assess progress in sequence alignment techniques. Evaluation measures that were dependent on comparison to a reference alignment were found to give good discrimination between methods. The STAMP Sc Score which is independent of a reference alignment also gave good discrimination. Application of OXBench in this paper shows that with the exception of T-COFFEE, the majority of the improvement in alignment accuracy seen since 1985 stems from improved pair-score matrices rather than algorithmic refinements. The maximum theoretical alignment accuracy obtained by pooling results over all methods was 94.5% with 52.5% accuracy for alignments in the 0-10 percentage identity range. This suggests that further improvements in accuracy will be possible in the future.
| S-EPMC280650 | biostudies-literature
Project description:The Clustal series of programs are widely used in molecular biology for the multiple alignment of both nucleic acid and protein sequences and for preparing phylogenetic trees. The popularity of the programs depends on a number of factors, including not only the accuracy of the results, but also the robustness, portability and user-friendliness of the programs. New features include NEXUS and FASTA format output, printing range numbers and faster tree calculation. Although, Clustal was originally developed to run on a local computer, numerous Web servers have been set up, notably at the EBI (European Bioinformatics Institute) (http://www.ebi.ac.uk/clustalw/).
| S-EPMC168907 | biostudies-literature
Project description:The use of sequence alignments to understand protein families is ubiquitous in molecular biology. High quality alignments are difficult to build and protein alignment remains one of the largest open problems in computational biology. Misalignments can lead to inferential errors about protein structure, folding, function, phylogeny, and residue importance. Identifying alignment errors is difficult because alignments are built and validated on the same primary criteria: sequence conservation. Local covariation identifies systematic misalignments and is independent of conservation. We demonstrate an alignment curation tool, LoCo, that integrates local covariation scores with the Jalview alignment editor. Using LoCo, we illustrate how local covariation is capable of identifying alignment errors due to the reduction of positional independence in the region of misalignment. We highlight three alignments from the benchmark database, BAliBASE 3, that contain regions of high local covariation, and investigate the causes to illustrate these types of scenarios. Two alignments contain sequential and structural shifts that cause elevated local covariation. Realignment of these misaligned segments reduces local covariation; these alternative alignments are supported with structural evidence. We also show that local covariation identifies active site residues in a validated alignment of paralogous structures. Loco is available at https://sourceforge.net/projects/locoprotein/files/.
| S-EPMC3371027 | biostudies-literature
Project description:BackgroundThe quality of multiple protein structure alignments are usually computed and assessed based on geometric functions of the coordinates of the backbone atoms from the protein chains. These purely geometric methods do not utilize directly protein sequence similarity, and in fact, determining the proper way to incorporate sequence similarity measures into the construction and assessment of protein multiple structure alignments has proved surprisingly difficult.ResultsWe present Formatt, a multiple structure alignment based on the Matt purely geometric multiple structure alignment program, that also takes into account sequence similarity when constructing alignments. We show that Formatt outperforms Matt and other popular structure alignment programs on the popular HOMSTRAD benchmark. For the SABMark twilight zone benchmark set that captures more remote homology, Formatt and Matt outperform other programs; depending on choice of embedded sequence aligner, Formatt produces either better sequence and structural alignments with a smaller core size than Matt, or similarly sized alignments with better sequence similarity, for a small cost in average RMSD.ConclusionsConsidering sequence information as well as purely geometric information seems to improve quality of multiple structure alignments, though defining what constitutes the best alignment when sequence and structural measures would suggest different alignments remains a difficult open question.
| S-EPMC3585936 | biostudies-literature
Project description:BackgroundProtein sequence alignment analyses have become a crucial step for many bioinformatics studies during the past decades. Multiple sequence alignment (MSA) and pair-wise sequence alignment (PSA) are two major approaches in sequence alignment. Former benchmark studies revealed drawbacks of MSA methods on nucleotide sequence alignments. To test whether similar drawbacks also influence protein sequence alignment analyses, we propose a new benchmark framework for protein clustering based on cluster validity. This new framework directly reflects the biological ground truth of the application scenarios that adopt sequence alignments, and evaluates the alignment quality according to the achievement of the biological goal, rather than the comparison on sequence level only, which averts the biases introduced by alignment scores or manual alignment templates. Compared with former studies, we calculate the cluster validity score based on sequence distances instead of clustering results. This strategy could avoid the influence brought by different clustering methods thus make results more dependable.ResultsResults showed that PSA methods performed better than MSA methods on most of the BAliBASE benchmark datasets. Analyses on the 80 re-sampled benchmark datasets constructed by randomly choosing 90% of each dataset 10 times showed similar results.ConclusionsThese results validated that the drawbacks of MSA methods revealed in nucleotide level also existed in protein sequence alignment analyses and affect the accuracy of results.
| S-EPMC6311937 | biostudies-literature
Project description:MotivationRecently, a range of new statistics have become available for the alignment-free comparison of two sequences based on k-tuple word content. Here, we extend these statistics to the simultaneous comparison of more than two sequences. Our suite of statistics contains, first, C(*)1 and C(S)1, extensions of statistics for pairwise comparison of the joint k-tuple content of all the sequences, and second, C(*)2, C(S)2 and C(geo)2, averages of sums of pairwise comparison statistics. The two tasks we consider are, first, to identify sequences that are similar to a set of target sequences, and, second, to measure the similarity within a set of sequences.ResultsOur investigation uses both simulated data as well as cis-regulatory module data where the task is to identify cis-regulatory modules with similar transcription factor binding sites. We find that although for real data, all of our statistics show a similar performance, on simulated data the Shepp-type statistics are in some instances outperformed by star-type statistics. The multiple alignment-free statistics are more sensitive to contamination in the data than the pairwise average statistics.AvailabilityOur implementation of the five statistics is available as R package named 'multiAlignFree' at be http://www-rcf.usc.edu/?fsun/Programs/multiAlignFree/multiAlignFreemain.html.Contactreinert@stats.ox.ac.uk.Supplementary informationSupplementary data are available at Bioinformatics online.
| S-EPMC3799466 | biostudies-literature
Project description:The importance of noncoding RNA sequences has become increasingly clear over the past decade. New RNA families are often detected and analyzed using comparative methods based on multiple sequence alignments. Accordingly, a number of programs have been developed for aligning and deriving secondary structures from sets of RNA sequences. Yet, the best tools for these tasks remain unclear because existing benchmarks contain too few sequences belonging to only a small number of RNA families. RNAconTest (RNA consistency test) is a new benchmarking approach relying on the observation that secondary structure is often conserved across highly divergent RNA sequences from the same family. RNAconTest scores multiple sequence alignments based on the level of consistency among known secondary structures belonging to reference sequences in their output alignment. Similarly, consensus secondary structure predictions are scored according to their agreement with one or more known structures in a family. Comparing the performance of 10 popular alignment programs using RNAconTest revealed that DAFS, DECIPHER, LocARNA, and MAFFT created the most structurally consistent alignments. The best consensus secondary structure predictions were generated by DAFS and LocARNA (via RNAalifold). Many of the methods specific to noncoding RNAs exhibited poor scalability as the number or length of input sequences increased, and several programs displayed substantial declines in score as more sequences were aligned. Overall, RNAconTest provides a means of testing and improving tools for comparative RNA analysis, as well as highlighting the best available approaches. RNAconTest is available from the DECIPHER website (http://DECIPHER.codes/Downloads.html).
| S-EPMC7161358 | biostudies-literature