New insights on the comma-less theory.

The comma-less hypothesis represents a theoretical effort to describe one of the steps in the early evolution of the translation apparatus. This hypothesis emphasizes the advantages that a RNY coding pattern would have provided in a primitive RNA adaptor-catalyst system. This theory has been debated for years, both in conceptual and statistical terms, and no consensus about its validity has been ascertained. In this work, a statistical model refuting this theory was reconsidered. This new approach eliminates the bias due to the absence of stop codons in the open reading frame, and to the amino acid composition of bacterial genes. The results obtained support the biological significance of the RNY coding pattern.     

Does the 'non-coding' strand code?

The hypothesis that DNA strands complementary to the coding strand contain in phase coding sequences has been investigated. Statistical analysis of the 50 genes of bacteriophage T7 shows no significant correlation between patterns of codon usage on the coding and non-coding strands. In Bacillus and yeast genes the correlation observed is not different from that expected with random synonymous codon usage, while a high correlation seen in 52 E. coli genes can be explained in terms of an excess of RNY codons. A deficiency of UUA, CUA and UCA codons (complementary to termination) seems to be restricted to the E. coli genes, and may be due to low abundance of the relevant cognate tRNA species. Thus the analysis shows that the non-coding strand has the properties expected of a sequence complementary to a coding strand, with no indications that it encodes, or may have encoded, proteins.     

Folding of small RNAs displaying the GNC base-pattern: implications for the self-organization of the genetic system

Theoretical arguments and statistical analyses of present-day coding sequences have long suggested the existence of primitive patterns in RNA sequences, which were thought to have been predominant at the time of the origin of the genetic code. The main propositions were centered around the base-patterns GNC and RNY, where R = A or G , Y = C or U and N = A, G, C or U. A theoretical model of the primitive process of translation explaining the origin of this type of pattern was recently published in the Journal of Theoretical Biology. On the basis of this previous analysis, and on physico-chemical evidence supporting the idea of the GNC base-pattern as the most primitive one, the present paper shows the results of folding simulations of small RNA strands displaying this pattern, which enabled us to specify the characteristics of the suggested primitive form of tRNA. This analysis is notably based on a conjecture of Eigen and Schuster of an early structural (or pattern) similarity between mRNA and tRNA, and, more specifically, of a "joint function of messenger and adaptor". Working with this conjecture, we show that the convergence of the primitive pool of RNAs toward a system containing a high proportion of sequences displaying the GNC base-pattern (according to the evolutionary model) is accompanied by a significant gain in stability of the translation process. In particular, it is demonstrated how the reading frame would be automatically discriminated without the presence of a start codon.     

Three-base periodicity patterns and self-similarity in whole bacterial chromosomes

It has been reported that in a collection of mRNAs the triplets GhN or RNY had a higher propensity to be separated by either three/six/nine, etc., bases than by two/four/five, etc., bases. This has been called three-base periodicity (TBP). In this work the frequency distribution of distances (FDDs) for all triplets in the Borrelia burgdorferi chromosome and selected triplets in other model sequences were determined. The FDDs produced oscillatory decaying patterns with TBP for most triplets and not only for those encompassed by the above formulas. Furthermore, we also found TBP for di- and mononucleotides. However, TBP was not observed for intergenic regions, sequences with a low content of coding regions or when the coding potential of sequences was disrupted by base shuffling. Excluding closely related species the FDDs between bacterial genomes were different and appeared characteristic of the analyzed genome. FDDs also showed self-similarity, since 1Mb sequences rendered FDDs that were very similar to those for the entire sequence.     

On the prevalence of certain codons (“RNY”) in genes for proteins

J.C. Shepherd notes that codons of the type RNY (R = purine, N = any nucleotide base, Y = pyrimidine) predominate over RNR in the genes for proteins. He has hypothesized that RNY codons are the relics of “a primitive code” composed of repeating RNY triplets. He found that RNY codons predominated in fourfold RNN codon sets (family boxes). These family boxes code for valine, threonine, alanine, and glycine. We argue that the proposed “comma-less” code composed of RNY never existed, and that, in any case, survival of such a code would have long since been erased by mutations. The excess of RNY codons in family boxes is probably attributable to preference for the corresponding tRNAs.     

A study of the purine/pyrimidine codon occurrence with a reduced centered variable and an evaluation compared to the frequency statistic

With the three-letter alphabet [R,Y,N] (R = purine, Y = pyrimidine, N = R or Y), there are 26 codons (NNN being excluded): RNN,...,NNY (six codons at two unspecified bases N), RRN,...,NYY (12 codons at one unspecified base N), RRR,...,YYY (eight specified codons). A statistical methodology that uses the codon frequency and a reduced centered variable leads to similar results for a codon occurrence study, regardless of gene function and regardless of a particular protein coding gene taxonomic population. Therefore, this variable can be considered a new codon usage index, whose use removes certain nonsignificant results found with the frequency statistic. This methodology identifies the common and rare codons (i.e., the codons having the highest and lowest occurrence) and leads to a model of codon evolution at three successive states: RNN, then RNY, and finally RYY. Some biological relations between this model and the YRY(N)6YRY preferential occurrence are also presented.     

Amplification of the sequences displaying the pattern RNY in the RNA world: the translation --> translation/replication hypothesis

Based on previous considerations published in J. theor. Biol., new analyses of the organization of the genetic system are reported in this paper. We show that theoretical considerations about the order observed in the genetic code table support the idea of a primitive self-aminoacylation process achieved by primordial tRNAs. The physico-chemical constraints connected with this process may explain why a primitive genetic system predominantly uses sequences with the codonic pattern RNN (R=purine; Y=pyrimidine; N=any of the four bases) to polymerize the amino acids into peptides through translation. These considerations lead us to propose the Translation --> Translation/Replication hypothesis, which may explain why only RNA sequences with the pattern RNY, instead of less restrictive RNN, are susceptible to amplification. Using these ideas, supported by properties of symmetry, features of the genetic code may be connected with the replication of specific RNA sequences in the RNA world.     

Predictive coding: a fresh view of inhibition in the retina

Interneurons exhibiting centre--surround antagonism within their receptive fields are commonly found in peripheral visual pathways. We propose that this organization enables the visual system to encode spatial detail in a manner that minimizes the deleterious effects of intrinsic noise, by exploiting the spatial correlation that exists within natural scenes. The antagonistic surround takes a weighted mean of the signals in neighbouring receptors to generate a statistical prediction of the signal at the centre. The predicted value is subtracted from the actual centre signal, thus minimizing the range of outputs transmitted by the centre. In this way the entire dynamic range of the interneuron can be devoted to encoding a small range of intensities, thus rendering fine detail detectable against intrinsic noise injected at later stages in processing. This predictive encoding scheme also reduces spatial redundancy, thereby enabling the array of interneurons to transmit a larger number of distinguishable images, taking into account the expected structure of the visual world. The profile of the required inhibitory field is derived from statistical estimation theory. This profile depends strongly upon the signal: noise ratio and weakly upon the extent of lateral spatial correlation. The receptive fields that are quantitatively predicted by the theory resemble those of X-type retinal ganglion cells and show that the inhibitory surround should become weaker and more diffuse at low intensities. The latter property is unequivocally demonstrated in the first-order interneurons of the fly's compound eye. The theory is extended to the time domain to account for the phasic responses of fly interneurons. These comparisons suggest that, in the early stages of processing, the visual system is concerned primarily with coding the visual image to protect against subsequent intrinsic noise, rather than with reconstructing the scene or extracting specific features from it. The treatment emphasizes that a neuron's dynamic range should be matched to both its receptive field and the statistical properties of the visual pattern expected within this field. Finally, the analysis is synthetic because it is an extension of the background suppression hypothesis (Barlow & Levick 1976), satisfies the redundancy reduction hypothesis (Barlow 1961 a, b) and is equivalent to deblurring under certain conditions (Ratliff 1965).     

Identification of protein-coding regions in Arabidopsis thaliana genome based on quadratic discriminant analysis

A new method (MZEF) for predicting internal coding exons in genomic DNA sequences has been developed. This method is based on a prediction algorithm that uses the quadratic discriminant function for multivariate statistical pattern recognition. With improved feature measures, an Arabidopsis thaliana-specific implementation of MZEF is completed and made available to the plant genome community.     

Periodicity of DNA in exons

Background  

The periodic pattern of DNA in exons is a known phenomenon. It was suggested that one of the initial causes of periodicity could be the universal (RNY) _n pattern (R = A or G, Y = C or U, N = any base) of ancient RNA. Two major questions were addressed in this paper. Firstly, the cause of DNA periodicity, which was investigated by comparisons between real and simulated coding sequences. Secondly, quantification of DNA periodicity was made using an evolutionary algorithm, which was not previously used for such purposes.     

Measuring the Coding Potential of Genomic Sequences Througha Combination of Triplet Occurrence Patterns and RNY Preference

The distribution of n-tuplet frequencies is shown to strongly correlate with functionality when examining a genomic sequence in a reading-frame specific manner. The approach described herein applies a coarse-graining procedure, which is able to reveal aspects of triplet usage that are related to protein coding, while at the same time remaining species independent, based on a simple summation of suitable triplet occurrences measures. These quantities are ratios of simple frequencies to suitable mononucleotide-frequency products promoting the incidence of the RNY motif, preferred in the most widely used codons. A significant distinction of coding and noncoding sequences is achieved.Reviewing Editor: Dr. Massimo Di Giulio     

Statistics, costs and rationality in ecological inference

The so-called 'null hypothesis' debate in ecology opened a statistical Pandora's Box. Ecologists were forced to question whether or not decades of pattern analysis had been productive. Over the past few years, the debate has expanded beyond the role of different kinds of statistical hypothesis to include the importance of different types of statistical error. Our objective in this article is to show how trends governing ecological inferences under uncertainty appear to be changing as ecologists become increasingly aware o f the potential importance of statistical errors.     

Selection pressures on codon usage in the complete genome of bacteriophage T7

Summary We searched the complete 39,936 base DNA sequence of bacteriophage T7 for nonrandomness that might be attributed to natural selection. Codon usage in the 50 genes of T7 is nonrandom, both over the whole code and among groups of synonymous codons. There is a great excess of purineany base-pyrimidine (RNY) codons. Codon usage varies between genes, but from the pooled data for the whole genome (12,145 codons) certain putative selective constraints can be identified. Codon usage appears to be influenced by host tRNA abundance (particularly in highly expressed genes), tRNA-mRNA interactions (one such interaction being perhaps responsible for maintaining the excess of RNY codons) and a lack of short palindromes. This last constraint is probably due to selection against host restriction enzyme recognition sites; this is the first report of an effect of this kind on codon usage. Selection against susceptibility to mutational damage does not appear to have been involved.     

Selection pressures on codon usage in the complete genome of bacteriophage T7

We searched the complete 39,936 base DNA sequence of bacteriophage T7 for nonrandomness that might be attributed to natural selection. Codon usage in the 50 genes of T7 is nonrandom, both over the whole code and among groups of synonymous codons. There is a great excess of purine- any base-pyrimidine (RNY) codons. Codon usage varies between genes, but from the pooled data for the whole genome (12,145 codons) certain putative selective constraints can be identified. Codon usage appears to be influenced by host tRNA abundance (particularly in highly expressed genes), tRNA-mRNA (one such interaction being perhaps responsible for maintaining the excess of RNY codons) and a lack of short palindromes. This last constraint is probably due to selection against host restriction enzyme recognition sites; this is the first report of an effect of this kind on codon usage. Selection against susceptibility to mutational damage does not appear to have been involved.     

Codon usage and secondary structure of MS2 phage RNA.

MS2 is an RNA bacteriophage (3569 bases). The secondary structure of the RNA has been determined, and is known to play an important role in regulating translation. Paired regions of the genome have a higher G+C content than unpaired regions. It has been suggested that this reflects selection for high G+C content to encourage pairing, but a re-analysis of the data together with computer simulation suggest that it is an automatic consequence in any RNA sequence of the way it folds up to minimise its free energy. It has also been suggested that the three registers in which pairing can occur in a coding region are used differentially to optimise the use of the redundancy of the genetic code, but re-analysis of the data shows only weak statistical support for this hypothesis.     

The distribution of selenium and mortality owing to acquired immune deficiency syndrome in the continental United States

A hypothesis has been proposed that Selenium (Se) concentration in the environment as measured by its uptake by alfalfa, which sorbs Se from the soil in proportion to what is present, exerted an apparent effect on incidence of (acquired immune deficiency syndrome) AIDS such that AIDS’ mortality within the conterminous United States was lower where the Se quantity in the soil was high than where the amount was low. The object of this study was to test this hypothesis for statistical significance and to discover whether the apparent pattern of AIDS mortality in relation to Se distribution holds true with respect to all ages, both races (Black and White), and both genders. The statistical analysis employed was analysis of variance. Age-specific data as well as age-adjusted data were subject to statistical analysis. Ages where AIDS mortality rates per 100,000 were greatest were in the range from 25–54 yr for low-, medium-, and high-Se areas of the US. Black mortality owing to AIDS showed highly statistically significant results for the three Se regions, both genders, and six age groups, whereas white mortality was not as significantly affected by Se. A hypothesis is proposed that the Black population during the last decade or so has been less migratory than the White population. Thus, their food supply and hence its Se content have been more stable than that of the White population, which is more prone to consume imported foods of unknown Se content and be more migratory. A second hypothesis is advanced that suggests that medical care is not equally available to the poor and especially poor Blacks. Black men and women die at a greater death rate than do Whites. This implies that a lack of medical care is the true cause. This article suggests that a pattern exists between the geographical distribution of Se using alfalfa as a dietary guide and AIDS’ mortality such that an inverse relationship persists between Se quantity in an area and AIDS’ mortality in the same area.     

Robust discriminant analysis and its application to identify protein coding regions of rice genes

Identification of protein coding regions is fundamentally a statistical pattern recognition problem. Discriminant analysis is a statistical technique for classifying a set of observations into predefined classes and it is useful to solve such problems. It is well known that outliers are present in virtually every data set in any application domain, and classical discriminant analysis methods (including linear discriminant analysis (LDA) and quadratic discriminant analysis (QDA)) do not work well if the data set has outliers. In order to overcome the difficulty, the robust statistical method is used in this paper. We choose four different coding characters as discriminant variables and an approving result is presented by the method of robust discriminant analysis.     

The Case for an Error Minimizing Standard Genetic Code

Since discovering the pattern by which amino acids are assigned to codons within the standard genetic code, investigators have explored the idea that natural selection placed biochemically similar amino acids near to one another in coding space so as to minimize the impact of mutations and/or mistranslations. The analytical evidence to support this theory has grown in sophistication and strength over the years, and counterclaims questioning its plausibility and quantitative support have yet to transcend some significant weaknesses in their approach. These weaknesses are illustrated here by means of a simple simulation model for adaptive genetic code evolution. There remain ill explored facets of the `error minimizing' code hypothesis, however, including the mechanism and pathway by which an adaptive pattern of codon assignments emerged, the extent to which natural selection created synonym redundancy, its role in shaping the amino acid and nucleotide languages, and even the correct interpretation of the adaptive codon assignment pattern: these represent fertile areas for future research.