Generic properties of combinatory maps: Neutral networks of RNA secondary structures

Random graph theory is used to model and analyse the relationship between sequences and secondary structures of RNA molecules, which are understood as mappings from sequence space into shape space. These maps are non-invertible since there are always many orders of magnitude more sequences than structures. Sequences folding into identical structures formneutral networks. A neutral network is embedded in the set of sequences that arecompatible with the given structure. Networks are modeled as graphs and constructed by random choice of vertices from the space of compatible sequences. The theory characterizes neutral networks by the mean fraction of neutral neighbors (λ). The networks are connected and percolate sequence space if the fraction of neutral nearest neighbors exceeds a threshold value (λ>λ*). Below threshold (λ<λ*), the networks are partitioned into a largest “giant” component and several smaller components. Structure are classified as “common” or “rare” according to the sizes of their pre-images, i.e. according to the fractions of sequences folding into them. The neutral networks of any pair of two different common structures almost touch each other, and, as expressed by the conjecture ofshape space covering sequences folding into almost all common structures, can be found in a small ball of an arbitrary location in sequence space. The results from random graph theory are compared to data obtained by folding large samples of RNA sequences. Differences are explained in terms of specific features of RNA molecular structures. Deicated to professor Manfred Eigen     

Hypervariable single and multi-locus DNA polymorphisms for genetic typing of non-human primates

The series of hypervariable, “minisatellite” loci characterized byJeffreys and coworkers in the human myoglobin gene have proved to be DNA sequences highly conserved throughout the eukaryotic genome, and hence the methodology developed for human DNA “fingerprinting” has found immediate application in an ever expanding number of species. Primatologists have not been slow to profit from a method which predicts individual recognition to a very high degree of probability, and initial studies have focused on paternity allocation (rather than paternity exclusion, as designated by the classical biochemical markers), adaptive aspects of socio-sexual behaviour patterns and mating systems. A number of probes with sequences corresponding to the common minisatellite core sequences have been used for probing genomic DNA, and synthetic, G-rich oligonucleotides (15 – 37 bases), corresponding to the core sequence of the minisatellite repeat unit, or simply di-, tri-, or tetranucleotide repeats, appear to be equally discriminatory. The multiple banding patterns produced on hybridization of these probes to restriction enzyme digests of DNA provide an advantage in that the probability of two unrelated individuals sharing the same banding pattern will be low. However, the uncertainty of linkage of the multiple loci identified precludes genotyping and population genetic analyses based on allele frequencies. In contrast, single locus analysis allows DNA typing using variable number tandem repeat (VNTR) or restriction fragment length (RFLP) DNA polymorphisms, and the merits and drawbacks relative to DNA fingerprinting are discussed. For the behavioural primatologists dealing with defined, accessible troops of primates, the value of multilocus DNA fingerprinting, in terms of established methodology and availability of probes applicable to species as phylogenetically wide-ranging as apes and prosimians, may well outweigh the loss of genotypic and population structure data.     

Scherrer and Jost’s symposium: the gene concept in 2008

Reconsideration of the term “gene” should take into account (a) the potential clash between hierarchical levels of information discussed in the 1970s by Gregory Bateson, (b) the contrast between conventional and genome phenotypes discussed in the 1980s by Richard Grantham, and (c) the emergence in the 1990s of a new science—Evolutionary Bioinformatics—that views genomes as channels conveying multiple forms of information through the generations. From this perspective, there is conceptual continuity between the functional “gene” of Mendel and today’s GenBank sequences. If the function attributed to a gene can change specifically as the result of a DNA mutation, then the mutated part of DNA can be considered as part of the gene. Conversely, even if appearing to locate within a gene, a mutation that does not change the specific function is not part of the gene, although it may change some other function to which the DNA sequence contributes. This strict definition is impractical, but serves as a guide to more workable, context-dependent, definitions. The gene is either (1) The DNA sequence that is transcribed, (2) The latter plus the immediate 5′ and 3′ sequences that, when mutated, specifically affect the function, (3) The latter two, plus any remote sequences that, when mutated, specifically affect the function. Attempts, such as that of Scherrer and Jost, to redefine Mendel’s “gene,” may be too narrowly focused on regulation to the exclusion of other important themes.     

The binding site for ribosomal protein L11 within 23 S ribosomal RNA of Escherichia coli

Ribosomal protein L11 of Escherichia coli was bound to 23 S rRNA and the resultant complex was digested with ribonuclease T1. A single RNA fragment, protected by protein L11, was isolated from such digests and was shown to rebind specifically to protein L11. The nucleotide sequence of this RNA fragment was examined by two-dimensional fingerprinting of ribonuclease digests. It proved to be 61 residues long and the constituent oligonucleotides could be fitted perfectly between residues 1052 and 1112 of the nucleotide sequence of E. coli 23 S rRNA.     

Periodicities in protein sequences

The correlation between various amino acid residues (either same or different), along the polypeptide chain have been studied using a large data base. A table of preference values for pairs having strong correlations has been constructed, which can be used to study any sequence and by calculating the weight of these sequences based on these preference values, a rough distinction between a “natural” and a “random” sequence can be made, One can further comment on the evolutionary status of proteins based on these weights.     

Imperfect complementarity and RNA structure

Intra- and intermolecular complementary contacts in RNA are not always perfect: a significant amount of mismatch pairs is frequently found in naturally occurring RNA helices. The state of art in studies on mismatch pairs and examples of imperfect complementarity are reviewed. Two more cases are revealed by nucleotide sequence analysis techniques: imperfect complementary contacts Between ends of intervening sequences in eukaryotic mRNA precursors, and possible “stickiness” of mRNA to the ribosomes. The “stickiness” might arise from specific 3-Base periodicity of protein coding sequences which is found to be as universal as the code itself. The imperfect complementary contacts between mRNA and rRNA which monitor the coding frame provide a structural basis for the explanation of leaky frameshift phenomena.     

Searching sequence databases via de novo peptide sequencing by tandem mass spectrometry

There are many computer programs that can match tandem mass spectra of peptides to database-derived sequences; however, situations can arise where mass spectral data cannot be correlated with any database sequence. In such cases, sequences can be automatically deduced de novo, without recourse to sequence databases, and the resulting peptide sequences can be used to perform homologous nonexact searches of sequence databases. This article describes details on how to implement both a de novo sequencing program called “Lutefisk,” and a version of FASTA that has been modified to account for sequence ambiguities inherent in tandem mass spectrometry data.     

Shifting ditypic site analysis: Heuristics for expanding the phylogenetic range of nucleotide sequences in Sankoff analyses

Summary We describe and illustrate a simple heuristic approach to the Sankoff methods for construction of parsimonious evolutionary trees from nucleotide sequence data. The procedure is intended to permit more valid inferences, particularly from relatively short sequences, concerning relationships among taxa separated for long time intervals. The procedure is based on the freat variability of evolutionary plasticity among sites in the molecules and removes from consideration the more highly variable sites. Editing is accomplished after classifying sites in carefully aligned arrays of sequences. Only “ditypic sites,” i.e., sites observed in only two evolutionary states within the array, are used in making phylogenetic inferences. This strategy makes possible the construction of good approximations to the most parsimonious Steiner strees, by means of efficient programs that require “dense species arrays,” i.e., species sets that differ from each other by relatively small numbers of differences in conservative sites. The technique is illustrated with 5S and 5.8S rRNA sequence data from published catalogs.     

Distinguished words in data sequences: Analysis and applications to neural coding and other fields

This paper concerns sequences of letters in which certain “distinguished” words are of interest. Such sequences arise as data in numerous fields including genetics and neuroscience. A probability distribution is given for the number of occurrences of a chosen word in a randomized sequence of letters. Such words are considered “favored” if they occur more than expected at random. Favored words have been discovered in nerve impulse trains and may reflect a neural coding scheme. This article is dedicated to my mother, Margaret Oakley Dayhoff, whose enthusiasm encouraged me to pursue research in mathematical biology.     

Diversity and distribution of the bioactive actinobacterial genus Salinispora from sponges along the Great Barrier Reef

Isolates from the marine actinobacterial genus Salinispora were cultured from marine sponges collected from along the length of the Great Barrier Reef (GBR), Queensland, Australia. Strains of two species of Salinispora, Salinispora arenicola and “Salinispora pacifica”, were isolated from GBR sponges Dercitus xanthus, Cinachyrella australiensis and Hyattella intestinalis. Phylogenetic analysis of the 16S rRNA gene sequences of representative strains, selected via BOX-PCR screening, identified previously unreported phylotypes of the species “S. pacifica”. The classification of these microdiverse 16S rRNA groups was further confirmed by analysis of the ribonuclease P RNA (RNase P RNA) gene through both phylogenetic and secondary structure analysis. The use of RNase P RNA sequences combined with 16S rRNA sequences allowed distinction of six new intraspecies phylotypes of “S. pacifica” within the geographical area of the GBR alone. One of these new phylotypes possessed a localised regional distribution within the GBR.     

A theory of steady-state activity in nerve-fiber networks II: The simple circuit

It is found that for a simple circuit of neurons, if this contains an odd number of inhibitory fibers, or none at all, or if the product of the activity parameters is less than unity, then the stimulus pattern always determines uniquely the steady-state activity. For circuits not of one of these types, it is possible to classify exclusively and exhaustively all possible activity patterns into three types, here called “odd”, “even”, and “mixed”. For any pattern of odd type and any pattern of even type there always exists a stimulus pattern consistent with both, but in no other way can such an association of activity patterns be made.     

Multisequence comparisons in protein coding genes

A very powerful method for detecting functional constraints operative in biological macromolecules is presented. This method entails performing a base permanence analysis of protein coding genes at each codon position simultaneously in different species. It calculates the degree of permanence of subregions of the gene by dividing it into segments,c codons long, counting how many sites remain unchanged in each segment among all species compared. By comparing the base permanence among several sequences with the expectations based on a stochastic evolutionary process, gene regions showing different degrees of conservation can be selected. This means that wherever the permanence deviates significantly from the expected value generated by the simulation, the corresponding regions are considered “constrained” or “hypervariable”. The constrained regions are of two types: α and β. The α regions result from constraints at the amino acid level, whereas the β regions are those probably involved in “control” processing. The method has been applied to mitochondrial genes coding for subunit 6 of the ATPase and subunit 1 of the cytochrome oxidase in four mammalian species: human, rat, mouse, and cow. In the two mitochondrial genes a few regions that are highly conserved in all codon positions have been identified. Among these regions a sequence, common to both genes, that is complementary to a strongly conserved region of 12S rRNA has been found. This method can also be of great help in studying molecular evolution mechanisms.     

Unique nucleotide sequence adjacent to the poly (A) region in yeast RNA

Yeast cells growing in a low phosphate medium were labeled with a pulse of ³²P_i or [³H]adenine and harvested after 15 minutes. Total RNA was extracted and digested with ribonuclease T₁. Poly(A)-rich fragments were isolated from the digest by hybridization to poly(U) impregnated fiberglass filters. Gel filtration showed the fragments to have a uniform chain length of about sixteen. Analysis of the composition gave (A₁₁, C₄, U). Complete pancreatic ribonuclease and partial spleen phosphodiesterase digests gave the sequence of the 5′ end of the fragment as CpApApUp-. Since the fragment was a ribonuclease T₁ product, the data points to a unique sequence of at least five residues, -GpCpApApUp-, adjacent to the poly(A)-rich terminus of pulse-labeled yeast mRNA. The remainder of the poly(A)-rich fragment consists of A residues with a few randomly interspaced C residues. The known specificity of yeast poly(A) polymerase can account for the presence of C residues in poly(A) tracts.     

Placozoa: at least two

It was shown that compensatory base changes (CBCs) in internal transcribed spacer 2 (ITS2) sequence-structure alignments can be used for distinguishing species. Using the ITS2 Database in combination with 4SALE — a tool for synchronous RNA sequence and secondary structure alignment and editing — in this study we present an in-depth CBC analysis for placozoan ITS2 sequences and their respective secondary structures. This analysis indicates at least two distinct species in Trichoplax (Placozoa) supporting a recently suggested hypothesis, that Placozoa is “no longer a phylum of one”. The first two authors contributed equally to this work.     

Dynamics of protein evolution

Protein sequences of the SWISS-PROT data bank were analysed by fractal techniques and harmonic analysis. In both cases, the results show the presence of self-affinity, a kind of self-similarity, in the sequences. Self-similarity is a sign of fractality and fractality is a consequence of a chaotic dynamical process. The evolution of the protein sequences is modelled as a dynamical system. The abundance of the fractal form in biology and creation of fractal forms as a result of “chaos” is already established. It may be noted that the word “chaos” here implies that most predictable processes can also become unpredictable under certain conditions, and that the most unpredictable processes are not as unpredictable as they are expected to be. In evolutionary dynamics, this allows scope for mutations and variations in otherwise predictable situations, potentially leading to increased diversity. Part of this work was presented at the National Symposium on Evolution of Life.     

A quantum model for controlled enzymic reactions: II. Controlled biochemical networks

Two control units, the switching and the two factor discriminating net are described. They are derived as a consequence of the enzymic oscillatory behavior induced by substrate “perturbation”. A complex network encompassing long sequences of metabolic reactions is constructed and the organization of cellular metabolic activities in well defined “regimes” and “states” inferred.     

The Jackprot Simulation Couples Mutation Rate with Natural Selection to Illustrate How Protein Evolution Is Not Random

Protein evolution is not a random process. Views which attribute randomness to molecular change, deleterious nature to single-gene mutations, insufficient geological time, or population size for molecular improvements to occur, or invoke “design creationism” to account for complexity in molecular structures and biological processes, are unfounded. Scientific evidence suggests that natural selection tinkers with molecular improvements by retaining adaptive peptide sequence. We used slot-machine probabilities and ion channels to show biological directionality on molecular change. Because ion channels reside in the lipid bilayer of cell membranes, their residue location must be in balance with the membrane’s hydrophobic/philic nature; a selective “pore” for ion passage is located within the hydrophobic region. We contrasted the random generation of DNA sequence for KcsA, a bacterial two-transmembrane-domain (2TM) potassium channel, from Streptomyces lividans, with an under-selection scenario, the “jackprot,” which predicted much faster evolution than by chance. We wrote a computer program in JAVA APPLET version 1.0 and designed an online interface, The Jackprot Simulation , to model a numerical interaction between mutation rate and natural selection during a scenario of polypeptide evolution. Winning the “jackprot,” or highest-fitness complete-peptide sequence, required cumulative smaller “wins” (rewarded by selection) at the first, second, and third positions in each of the 161 KcsA codons (“jackdons” that led to “jackacids” that led to the “jackprot”). The “jackprot” is a didactic tool to demonstrate how mutation rate coupled with natural selection suffices to explain the evolution of specialized proteins, such as the complex six-transmembrane (6TM) domain potassium, sodium, or calcium channels. Ancestral DNA sequences coding for 2TM-like proteins underwent nucleotide “edition” and gene duplications to generate the 6TMs. Ion channels are essential to the physiology of neurons, ganglia, and brains, and were crucial to the evolutionary advent of consciousness. The Jackprot Simulation illustrates in a computer model that evolution is not and cannot be a random process as conceived by design creationists.     

Models on prebiotic polymer competition: A deterministic approach

Two simple models are proposed and analysed, in which it is shown that the formation of a new polymer, resulting from an “error” in the template action mechanism of production of an old polymer, may compromise the stability of the initial system under specific conditions, in the context of prebiotic evolution. Autocatalysis is shown to be a “selective advantage”, enabling the “mutant” to dominate in concentration and even replace the initial polymer. The addition of a third molecule playing the role of a catalyst causes hysteresis effects.     

A topological study of the base sequences of MS2 and ϕX174 genoma

A correlation matrix analysis is applied to the base sequence of MS2 and ϕX174 in comparison with sets of simulated sequences with different degrees of constaint Significant differences between a codified sequence, and a statistical one in terms of the “correlation matrix” for sets of different length cannot be found. This result is analysed in terms of nucleotide sequences with different levels of informational content.     

Typostrophism in Palaeozoic Ammonoids?

The anti-Darwinian “Typostrophe Theory” of O.H.Schindewolf can be put to the test by revisiting the ammonoid examples on which this macroevolutionary model was founded. It is shown that none of the three theoretical elements saltationism, internalism, and cyclism can be supported by empirical data obtained from ammonoid research. Putative saltations (“Typogenesis”) were feigned because of the lack of knowledge of intermediate forms. Internalistic and orthogenetic development (“Typostasis”) can only be favoured by neglecting possible functions of morphological characters. Preprogrammed extinction of “degenerated” clades (“Typolysis”) is unlikely when ruling out anthropocentric views regarding ammonoid morphology. In terms of evolution of Palaeozoic ammonoids, there is no basis for the preference of the “Typostrophe Theory” or some of its composing elements, including the “Type Concept” and “Proterogenesis”, over the Darwinian evolutionary model and the Modern Synthesis.