Graphical coding of nucleic acid sequences

When, in a nucleic acid sequence, the four letters C, G, A, T (or U) are replaced by suitable graphical symbols, some patterns become immediately apparent. Two sets of symbols, constructed for the analysis of either purine/pyrimidine alternations, or of regions of complementarity within a sequence are shown. In addition, another mode of coding is presented, in which the four letters are represented by vectors. The sequence is thus transformed into a planar trajectory. We show, in the case of the gene for human beta hemoglobin, that such a coding enables an easy discrimination between introns and exons.     

Rational recognition of nucleic acid sequences

Recent progress in synthetic and computational chemistry has made it possible to develop certain novel drug candidates. Drug candidates for genetic diseases, such as cancer, may also be designed on the basis of structural information obtained using X-ray analysis and NMR, as well as evidence from biological techniques applied to natural products - DNA (or RNA) complexes and conjugates. The resulting designed drug candidates exhibit promising performance based on the recognition on nucleic acid sequences.     

Matching relational patterns in nucleic acid sequences

We describe a program that efficiently searches sequence databanks for complex patterns where sites are linked by commonrelations such as identity, complementarity or span. Its algorithmis closer to those of automatic demonstration than to the finitestate machines used in fast pattern matching. The repertoryof relations can be enriched at will without rewriting the coreof the program. The program is written in Pascal-ISO and runson a microcomputer. Received on September 25, 1986; accepted on April 30, 1987     

Regulatory pattern identification in nucleic acid sequences

In addition to the sequence homologies and statistical patterns identified among numerous genetic sequences, there are subtler classes of patterns for which most current computer search methods offer very limited utility. This class includes various presumptive eukaryotic regulatory sites. A critique of the often employed consensus and local homology methods suggests the need for new tools. In particular, such new methods should use the positional and structural data now becoming available on exactly what it is that is recognized in the DNA sequence by sequence-specific binding proteins.     

Recognition of ill-defined signals in nucleic acid sequences

A set of programs has been developed for the definition andhandling of nucleic acid sequence consensus information. Thesequences of known genetic control signals are combined in amatrix. The origins and positions of the signals are recorded.Old matrices can be updated dynamically: new signals are includedand obsolete ones deleted. Matrices of several different typesare computed optionally. Several of these matrices can be combinedto find possible new signals. The use of matrices allows theexact quantification of signal qualities. The described programsare part of a program library named GENEXPERT. Application examplesgiven are the search for tRNA genes and the search for promotersin the bacteriophage genome. Received on July 22, 1987; accepted on October 5, 1987     

29 Accelerating nucleic acid design using pre-selected sequences

Nanoscale nucleic acids could potentially be designed to be catalysts, pharmaceuticals, or probes for detecting pathogens. We hypothesize that designing nucleic acid molecules from pre-selected sequences, rather than from random sequences, would increase the speed of designing large molecules and also increase the accuracy of design. Helices should be formed in the optimal folding free energy change range, have maximal structure probability, and minimal ensemble defect. Loops should be composed of sequences with the lowest ensemble free energy change. All sequences should have low tendency to cross- and self-hybridize. These features are observed in RNA sequences with known structure.We demonstrate that preselected sequences and accelerate the design of structures that are mimics of biologically relevant structures. This is implemented as a new structure design component of RNAstructure (http://rna.urmc.rochester.edu/RNAstructure.html). This work is a collaboration with Celadon Laboratories, Inc. (http://www.celadonlabs.com/).     

Methods for discovering novel motifs in nucleic acid sequences

We describe a computer tool to aid the discovery of new motifsin nucleic acid sequences. A typical use would be to analysea set of upstream regions from a family of related genes inorder to find possible control sequences. The heart of the methodis the creation of dictionaries of related subsequences. Thesedictionaries can then be analysed to look for the commonestor best-defined subsequences, those that occur in the highestnumber of different sequences, or for those in equivalent positionswithin the family. We show the application of the method toa set of E. coli promoter sequences. Received on May 9, 1989; accepted on July 27, 1989     

JaDis: computing distances between nucleic acid sequences.

SUMMARY: JaDis is a Java application for computing evolutionary distances between nucleic acid sequences and G+C base frequencies. It allows specific comparison of coding sequences, of non-coding sequences or of a non-coding sequence with coding sequences. AVAILABILITY: http://pbil.univ-lyon1.fr/software/jadis.html     

A method to find palindromes in nucleic acid sequences

Various types of sequences in the human genome are known to play important roles in different aspects of genomic functioning. Among these sequences, palindromic nucleic acid sequences are one such type that have been studied in detail and found to influence a wide variety of genomic characteristics. For a nucleotide sequence to be considered as a palindrome, its complementary strand must read the same in the opposite direction. For example, both the strands i.e the strand going from 5'' to 3'' and its complementary strand from 3'' to 5'' must be complementary. A typical nucleotide palindromic sequence would be TATA (5'' to 3'') and its complimentary sequence from 3'' to 5'' would be ATAT. Thus, a new method has been developed using dynamic programming to fetch the palindromic nucleic acid sequences. The new method uses less memory and thereby it increases the overall speed and efficiency. The proposed method has been tested using the bacterial (3891 KB bases) and human chromosomal sequences (Chr-18: 74366 kb and Chr-Y: 25554 kb) and the computation time for finding the palindromic sequences is in milli seconds.     

De novo design of sequences for nucleic acid structural engineering

An interactive procedure has been developed to assign sequences for the design of nucleic acid secondary structure. The primary goal of the procedure is to facilitate macromolecular architecture studies through the design of branched nucleic acid mono- and oligo-junction constructs in a convenient fashion. The essential feature of the sequence-symmetry minimization algorithm employed is the treatment of short sequences as vocabulary elements whose repetition decreases control over the resulting secondary structure. Both manual and semi-automatic application of this approach are available. The design of linear nucleic acid molecules or molecules containing single-stranded loops or connectors is also possible through application of the procedure.     

Prebiotically plausible mechanisms increase compositional diversity of nucleic acid sequences

During the origin of life, the biological information of nucleic acid polymers must have increased to encode functional molecules (the RNA world). Ribozymes tend to be compositionally unbiased, as is the vast majority of possible sequence space. However, ribonucleotides vary greatly in synthetic yield, reactivity and degradation rate, and their non-enzymatic polymerization results in compositionally biased sequences. While natural selection could lead to complex sequences, molecules with some activity are required to begin this process. Was the emergence of compositionally diverse sequences a matter of chance, or could prebiotically plausible reactions counter chemical biases to increase the probability of finding a ribozyme? Our in silico simulations using a two-letter alphabet show that template-directed ligation and high concatenation rates counter compositional bias and shift the pool toward longer sequences, permitting greater exploration of sequence space and stable folding. We verified experimentally that unbiased DNA sequences are more efficient templates for ligation, thus increasing the compositional diversity of the pool. Our work suggests that prebiotically plausible chemical mechanisms of nucleic acid polymerization and ligation could predispose toward a diverse pool of longer, potentially structured molecules. Such mechanisms could have set the stage for the appearance of functional activity very early in the emergence of life.     

Ultrastructural localization of nucleic acid sequences in Saccharomyces cerevisiae nucleoli

The putative nucleolus in Saccharomyces cerevisiae is visible in electron micrographs as a darkly stained, crescent-shaped structure associated with the nuclear envelope. The haploid yeast genome contains 100 200 tandem copies of a 9.1 kb ribosomal DNA (rDNA) repeat predicted to reside in this structure. We combined in situ hybridization of non-isotopically labeled probes to isolated S. cerevisiae nuclei with immunogold detection to localize rDNA and rRNA precursor sequences in nuclei at the electron microscope (EM) level. Gold particles are restricted to defined regions of nuclei which appear more electron dense than the bulk of the nucleus and which generally exhibit the crescent shape typical of the structure thought to be the nucleolus. In addition, snR17, the yeast homolog of mammalian U3, a nucleolar-restricted small nuclear RNA (snRNA), was localized to the same electron dense region of the nucleus. These data, in conjunction with published immunofluorescent localizations of nucleolarassociated antigens, provide definitive proof that the dense crescent is the nucleolus. Finally, the technique described is applicable to probing nuclear organization in a genetically manipulable system.Abbreviations snRNA small nuclear RNA - AAF N-acetoxy-2-acetyl-aminofluorenceby M.L. Pardue     

Efficient algorithms for folding and comparing nucleic acid sequences.

Fast algorithms for analysing sequence data are presented. An algorithm for strict homologies finds all common subsequences of length greater than or equal to 6 in two given sequences. With it, nucleic acid pieces five thousand nucleotides long can be compared in five seconds on CDC 6600. Secondary structure algorithms generate the N most stable secondary structures of an RNA molecule, taking into account all loop contributions, and the formation of all possible base-pairs in stems, including odd pairs (G.G., C.U., etc.). They allow a typical 100-nucleotide sequence to be analysed in 10 seconds. The homology and secondary structure programs are respectively illustrated with a comparison of two phage genomes, and a discussion of Drosophila melanogaster 55 RNA folding.     

A rapid method of searching for homology of nucleic acid sequences

A new method of the homology search between DNA sequences was suggested. This method may be used to find extensive and not strong homologies with point mutations and deletions. The computer time to compare sequences is less than dynamic program algorithms at least by four orders of magnitude. It makes possible to use the method for homology search all over the nucleotide bank by personal computers. Some results of homology search are presented.     

A proposal on metrics for identification using nucleic acid sequences

Abstract The need is stressed for attempts to be made to permit diagnostic nucleic acid sequences to be used in a quantitative manner. Sequence differences or binding values should be converted to a distance measure and from this an ultrametric tree should be constructed. A single quantitative determination can yield considerable information about the likely identity of an unknown microorganism when the distance obtained from the sequence is compared with the tree. The concept is illustrated by hypothetical species and genus subsequences, and it is suitable both for successive use of hierarchical subsequences and for automated identification. It is pointed out that entirely specific subsequences for higher taxa may be difficult to discover. These principles will be useful for the future design of diagnostic sequences, including possible application to DNA-DNA pairing.     

Dampable waves along nucleic acid sequences mediating nucleotides' interactions.

This work studied the relationship of any two nucleotides in genomic sequences, coding sequences and full-length cDNAs. We made a statistical hypothesis that there exist no interactions between any two nucleotides in sequences, therefore, a hypothetical combination distribution of two nucleotides is considered and the difference between the hypothetical combination distribution and the actual distribution is used to measure the average interaction between the two nucleotides. As a result, we found that the interactions between any two nucleotides are clearly and closely related with dampable wavelike patterns along the sequences. Based on the results we daringly make some hypotheses on several biological topics. Further, studies on the wave may provide new clues for gene prediction and genome structure study.     

Comparative analysis of nucleic acid sequences by their general constraints.

We describe two measures of a nucleic acid sequence, derived from Information Theory, which characterize the constraints toward nonuniform base composition, and the constraints on the ordering of the bases. These two measures distinguish extra-chromosomal coding sequences from all other coding sequences examined. The two measures separate eukaryotic coding sequences into two groups: those with introns and those without introns. We have also found a relationship between the general constraints of a subsequence and its degree of conservation in related genes.