A genetic algorithm for multiple molecular sequence alignment

MOTIVATION: Multiple molecular sequence alignment is among the most important and most challenging tasks in computational biology. The currently used alignment techniques are characterized by great computational complexity, which prevents their wider use. This research is aimed at developing a new technique for efficient multiple sequence alignment. APPROACH: The new method is based on genetic algorithms. Genetic algorithms are stochastic approaches for efficient and robust searching. By converting biomolecular sequence alignment into a problem of searching for optimal or near-optimal points in an 'alignment space', a genetic algorithm can be used to find good alignments very efficiently. RESULTS: Experiments on real data sets have shown that the average computing time of this technique may be two or three orders lower than that of a technique based on pairwise dynamic programming, while the alignment qualities are very similar. AVAILABILITY: A C program on UNIX has been written to implement the technique. It is available on request from the authors.     

Progressive multiple alignment with constraints

A progressive alignment algorithm produces a multialignment of a set of sequences by repeatedly aligning pairs of sequences and/or previously generated alignments. We describe a method for guaranteeing that the alignment generated by a progressive alignment strategy satisfies a user-specified collection of constraints about where certain sequence positions should appear relative to others. Our main result is an algorithm to compute just the "prime" constraints that are implied by the user-given constraints; these are shown to be precisely the constraints that the alignment algorithm must obey. In practice, the time required to handle constraints is negligible and frequently much less than the time saved because the constraints permit searching a restricted region of the dynamic-programming grid. An alignment of the beta-like globin gene cluster of several mammals illustrates the practicality of the method.     

Multiple sequence alignment with Clustal X

Platelet activating factor (PAF) is a phospholipid mediator of inflammation and stimulates anion secretion in animals and in isolated preparations of human colon. Nitric oxide (NO), synthesized from the amino acid L-arginine, is an important enteric inhibitory neurotransmitter. In addition, NO-donating compounds stimulate anion secretion in rat and guinea-pig colon. In this article, Angelo A. Izzo and colleagues review the key pharmacological features of the involvement of NO and PAF in the action of laxatives and propose that the classification of laxatives should take into account the important implications of these endogenous mediators.     

Gene recognition via spliced sequence alignment

Gene recognition is one of the most important problems in computational molecular biology. Previous attempts to solve this problem were based on statistics, and applications of combinatorial methods for gene recognition were almost unexplored. Recent advances in large-scale cDNA sequencing open a way toward a new approach to gene recognition that uses previously sequenced genes as a clue for recognition of newly sequenced genes. This paper describes a spliced alignment algorithm and software tool that explores all possible exon assemblies in polynomial time and finds the multiexon structure with the best fit to a related protein. Unlike other existing methods, the algorithm successfully recognizes genes even in the case of short exons or exons with unusual codon usage; we also report correct assemblies for genes with more than 10 exons. On a test sample of human genes with known mammalian relatives, the average correlation between the predicted and actual proteins was 99%. The algorithm correctly reconstructed 87% of genes and the rare discrepancies between the predicted and real exon-intron structures were caused either by short (less than 5 amino acids) initial/terminal exons or by alternative splicing. Moreover, the algorithm predicts human genes reasonably well when the homologous protein is nonvertebrate or even prokaryotic. The surprisingly good performance of the method was confirmed by extensive simulations: in particular, with target proteins at 160 accepted point mutations (PAM) (25% similarity), the correlation between the predicted and actual genes was still as high as 95%.     

A polyhedral approach to RNA sequence structure alignment

Ribonucleic acid (RNA) is a polymer composed of four bases denoted A, C, G, and U. It generally is a single-stranded molecule where the bases form hydrogen bonds within the same molecule leading to structure formation. In comparing different homologous RNA molecules it is important to consider both the base sequence and the structure of the molecules. Traditional alignment algorithms can only account for the sequence of bases, but not for the base pairings. Considering the structure leads to significant computational problems because of the dependencies introduced by the base pairings. In this paper we address the problem of optimally aligning a given RNA sequence of unknown structure to one of known sequence and structure. We phrase the problem as an integer linear program and then solve it using methods from polyhedral combinatorics. In our computational experiments we could solve large problem instances--23S ribosomal RNA with more than 1400 bases--a size intractable for former algorithms.     

A symmetric-iterated multiple alignment of protein sequences

A new symmetric-iterative method for multiple alignment of protein sequences is presented. The method can be described as a combination of motif finding and dynamic programming procedures. It uses each sequence as a standard to which all sequences are aligned based on the significant segment pair alignment (SSPA) protocol. Sequences are further matched using a reduced scoring threshold to provide fillers and extensions between highly significant segment pair matches. The method produces alignment blocks that accommodate indels and are separated by variable-length unaligned segments. Construction of consensus sequences is iterative, assigning greater weights to more distantly related sequences. A consensus sequence and various measures of conservation at each aligned position can be used for comparisons between protein families, for data base searches, and for analysis of functional and evolutionary features. The method is illustrated on the extended family of prokaryotic and eukaryotic RecA-like sequences. The RecA-like sequences reveal extended alignments among eubacterial RecA and separately among eukaryotic/archaebacterial Rad51/RadA. Eleven conserved blocks are common to both groups, two of them encompassing the ATP-binding A and B-sites. Among the most conserved positions are glycine residues. For example, they occur twice as doublets putatively serving as hinge connections that provide opportunity for alternative structural conformations. Also several charged/polar residues are highly conserved, probably consequent upon the extensive intermonomer interactions in RecA/Rad51 filament formation and possibly relevant protein-protein and protein-nucleic acid interactions.     

Flexible algorithm for direct multiple alignment of protein structures and sequences

The recently described equivalence between the alignment of two proteins and a conformation of a lattice chain on a two-dimensional square lattice is extended to multiple alignments. The search for the optimal multiple alignment between several proteins, which is equivalent to finding the energy minimum in the conformational space of a multi-dimensional lattice chain, is studied by the Monte Carlo approach. This method, while not deterministic, and for two-dimensional problems slower than dynamic programming, can accept arbitrary scoring functions, including non-local ones, and its speed decreases slowly with increasing number of dimensions. For the local scoring functions, the MC algorithm can also reproduce known exact solutions for the direct multiple alignments. As illustrated by examples, both for structure- and sequence-based alignments, direct multi-dimensional alignments are able to capture weak similarities between divergent families much better than ones built from pairwise alignments by a hierarchical approach.     

Normalization of affine gap costs used in optimal sequence alignment

The ionophore A23187 was used to facilitate release and continued development of Anaplasma marginale in short-term erythrocyte cultures. Addition of 10 microM A23187 to the cultures resulted in significant decrease in percentage of parasitized erythrocytes (PPE) by 24 hours after treatment; further development and increase in PPE was not observed. In contrast, the PPE of untreated cultures, those treated with dimethyl sulfoxide (DMSO) only and with 1 microM A23187 increased slightly during that time. Total erythrocyte count decreased in treated cultures in excess of that expected after samples of the medium were taken for analysis. The greatest cell loss and increased hemoglobin concentration in culture medium was observed in cultures treated with 10 microM A23187 and with an equivalent volume of DMSO. The DMSO appeared to cause hemolysis of some erythrocytes, but not of infected cells selectively. Release of A marginale inclusion bodies was seen by electron microscopy in samples from the 10 microM A23187-exposed cultures. At 30 minutes after treatment, free initial bodies were frequently seen. Inclusion body membranes and individual A marginale were associated with membranes of adjacent erythrocytes. Individual rickettsiae were seen in cell depressions and appeared to be entering erythrocytes. However, neither further invasion nor development of the parasite in erythrocytes was observed. Ionophore A23187 appeared to promote release of A marginale from erythrocytes, but did not enhance infection of erythrocytes or development of organisms in vitro.     

COFFEE: an objective function for multiple sequence alignments

MOTIVATION: In order to increase the accuracy of multiple sequence alignments, we designed a new strategy for optimizing multiple sequence alignments by genetic algorithm. We named it COFFEE (Consistency based Objective Function For alignmEnt Evaluation). The COFFEE score reflects the level of consistency between a multiple sequence alignment and a library containing pairwise alignments of the same sequences. RESULTS: We show that multiple sequence alignments can be optimized for their COFFEE score with the genetic algorithm package SAGA. The COFFEE function is tested on 11 test cases made of structural alignments extracted from 3D_ali. These alignments are compared to those produced using five alternative methods. Results indicate that COFFEE outperforms the other methods when the level of identity between the sequences is low. Accuracy is evaluated by comparison with the structural alignments used as references. We also show that the COFFEE score can be used as a reliability index on multiple sequence alignments. Finally, we show that given a library of structure-based pairwise sequence alignments extracted from FSSP, SAGA can produce high-quality multiple sequence alignments. The main advantage of COFFEE is its flexibility. With COFFEE, any method suitable for making pairwise alignments can be extended to making multiple alignments. AVAILABILITY: The package is available along with the test cases through the WWW: http://www. ebi.ac.uk/cedric CONTACT: cedric.notredame@ebi.ac.uk     

Phase alignment of multiple surface coil data for reduced bandwidth and reconstruction requirements

Multiple element surface coils are often used in clinical MRI to increase the image signal-to-noise ratio (S/N). Use of multicoils typically requires increased net sampling bandwidth and data processing for each coil element. A phase-alignment technique is described which combines the signals from all coil elements before image reconstruction, greatly relaxing the technical requirements of the standard multicoil methods. Hardware and software implementations allow reduction of the reconstruction requirement to that of a single coil. The hardware implementation additionally allows a significant reduction in the net sampling bandwidth. The method is applicable to high speed MRI techniques, as demonstrated in phantoms and volunteers.     

New approaches for managing stress incontinence in women

Stress urinary incontinence is a problem for one in four women seen in the primary care setting. The incontinence usually is not identified as women do not view it as a problem, do not seek treatment, and turn to self-care practices. Technology in product development is evolving that can assist women in managing their incontinence. This article reviews new innovations in treatment that can be recommended by primary care providers.     

New approaches for treatment of systemic lupus erythematosus

Each of the new approaches to treating SLE offers some hope in the ongoing effort to respond effectively to the challenges of this debilitating and often lethal condition. Research is extremely active and promises to accelerate as more is learned.     

New approaches in vaccine development

BACKGROUND: A prospective study was carried out at the University Hospital, Kuala Lumpur to determine the cervical carriage rate of Ureaplasma urealyticum and Mycoplasma hominis among healthy pregnant women at delivery and the incidence of nasopharyngeal colonisation among their infants. PATIENTS: Sixty mother and baby pairs were examined. RESULTS: Cervical colonisation among the mothers was found to be 56.7% for U.urealyticum and 17.7% for M.hominis. The transmission rate to their infants was 88.2% and 30% for U.urealyticum and M.hominis respectively. CONCLUSION: There was no statistically significant difference in the maternal colonisation rates according to ethnic group, parity and past history of abortion. All U.urealyticum isolates in our study were sensitive to erythromycin but about one-third were resistant to tetracycline and ciprofloxacin and 26.5% were resistant to minocycline.     

New and old treatments for multiple sclerosis

Audiogenic seizures associated with loss of weight, prostration, piloerection, palpebral ptosis and motor deficiency were induced after sound stimulation of determined frequency and amplitude in magnesium-deficient DBA/2 mice. These symptoms were maintained when standard diet conditions (1700 ppm Mg2+) were restored. In contrast, mice were protected from audiogenic seizure in a dose related manner when Crassostrea gigas extract (JCOE) were added to the diet for 10 consecutive days. Although a rational explanation for this protective effect has not yet been determined, it is assumed that it might be due to a chelating complex formed between Mg2+ and taurine, which enhance the uptake of Mg2+.     

Multiple sequence alignment in HTML: colored, possibly hyperlinked, compact representations

Protein sequence alignments are widely used in protein structure prediction, protein engineering, modeling of proteins, etc. This type of representation is useful at different stages of scientific activity: looking at previous results, working on a research project, and presenting the results. There is a need to make it available through a network (intranet or WWW), in a way that allows biologists, chemists, and noncomputer specialists to look at the data and carry on research--possibly in a collaborative research. Previous methods (text-based, Java-based) are reported and their advantages are discussed. We have developed two novel approaches to represent the alignments as colored, hyper-linked HTML pages. The first method creates an HTML page that uses efficiently the image cache mechanism of a WWW browser, thereby allowing the user to browse different alignments without waiting for the images to be loaded through the network, but only for the first viewed alignment. The generated pages can be browsed with any HTML2.0-compliant browser. The second method that we propose uses W3C-CSS1-style sheets to render alignments. This new method generates pages that require recent browsers to be viewed. We implemented these methods in the Viseur program and made a WWW service available that allows a user to convert an MSF alignment file in HTML for WWW publishing. The latter service is available at http:@www.lctn.u-nancy.fr/viseur/services.htm l.     

提高焦炭质量的新技术措施

随着高炉的大型化和高喷煤低焦比操作,对焦炭的质量要求逐步提高,从炼焦工艺分析,目前提高焦炭质量的工艺手段主要有成型煤、煤调湿、分组粉碎、火落管理和干熄焦等,从未来发展趋势来看需要进一步提高工艺手段,提高焦炭质量的针对性和有效性。