Class I release factors in ciliates with variant genetic codes

In eukaryotes with the universal genetic code a single class I release factor (eRF1) most probably recognizes all stop codons (UAA, UAG and UGA) and is essential for termination of nascent peptide synthesis. It is well established that stop codons have been reassigned to amino acid codons at least three times among ciliates. The codon specificities of ciliate eRF1s must have been modified to accommodate the variant codes. In this study we have amplified, cloned and sequenced eRF1 genes of two hypotrichous ciliates, Oxytricha trifallax (UAA and UAG for Gln) and Euplotes aediculatus (UGA for Cys). We also sequenced/identified three protist and two archaeal class I RF genes to enlarge the database of eRF1/aRF1s with the universal code. Extensive comparisons between universal code eRF1s and those of Oxytricha, Euplotes, and Tetrahymena which represent three lineages that acquired variant codes independently, provide important clues to identify stop codon-binding regions in eRF1. Domain 1 in the five ciliate eRF1s, particularly the TASNIKS heptapeptide and its adjacent region, differs significantly from domain 1 in universal code eRF1s. This observation suggests that domain 1 contains the codon recognition site, but that the mechanism of eRF1 codon recognition may be more complex than proposed by Nakamura et al. or Knight and Landweber.     

Nonstandard genetic codes and translation termination

Genetic code is not universal. Various nonstandard versions of the code are known for some mitochondrial, prokaryotic, and eukaryotic genomes. The most common deviation is stop codon reassignment; i.e., a stop codon is decoded as a sense codon rather than as a signal for translation termination. Class 1 release factors (RFs: prokaryotic RF1 and RF2 and eukaryotic eRF1) recognize the stop codons and induce hydrolysis of peptidyl-tRNA in the ribosome. The specificity of class 1 RFs changes in organisms with a nonstandard code. The rare amino acids selenocysteine and pyrrolysine utilize essentially different decoding strategies. The review considers several hypotheses of the origin of nonstandard genetic codes. A new hypothesis is advanced, assuming a change in the specificity of class 1 RFs as a starting point for stop codon reassignment.     

The role of alternative genetic codes in viral evolution and emergence

Although the ‘universal’ genetic code is widespread among life-forms, a number of diverse lineages have evolved unique codon reassignments. The proteomes of these organisms and organelles must, by necessity, use the same codon assignments. Likewise, for an exogenous genetic element, such as an infecting viral genome, to be accurately and completely expressed with the host's translation system, it must employ the same genetic code. This raises a number of intriguing questions regarding the origin and evolution of viruses. In particular, it is extremely unlikely that viruses of hosts utilizing the universal genetic code would emerge, via cross-species transmission, in hosts utilizing alternative codes, and vice versa. Consequently, more parsimonious scenarios for the origins of such viruses include the prolonged co-evolution of viruses with cellular life, or the escape of genetic material from host genomes. Further, we raise the possibility that emerging viruses provide the selection pressure favoring the use of alternative codes in potential hosts, such that the evolution of a variant genetic code acts as a unique and powerful antiviral strategy. As such, in the face of new emerging viruses, hosts with codon reassignments would have a significant selective advantage compared to hosts utilizing the universal code.     

Non-standard genetic codes and translation termination

Genetic code is not universal. Various non-standard versions of the code were found in mitochondrial, prokaryotic and eukaryotic genomes. Stop codons are used to signal the ribosome stop translation of the coding sequence and prone to reassignment to sense codons. Class-1 termination factors recognize stop codons and promote hydrolysis of the peptidyl-tRNA in ribosome (RF1, RF2 in prokaryotes and eRF1 in eukaryotes). The class-1 factor termination specificity is changed in non-standart codes organisms. Pyrrolysine and selenocysteine use dissimilar decoding strategies. The various non-standart code origin hypotheses are described. It was proposed that specificity alteration of the class-1 release factor was a starting point for stop codon reassignment.     

Genetic codes as evolutionary filters: subtle differences in the structure of genetic codes result in significant differences in patterns of nucleotide substitution

The codon-degeneracy model (CDM) predicts that patterns of nucleotide substitution in protein-coding genes are largely determined by the relative frequencies of four-fold (4f), two-fold, and non-degenerate sites, the attributes of which are determined by the structure of the governing genetic code. The CDM thus further predicts that genetic codes with alternative structures will "filter" molecular evolution differentially. A method, therefore, is presented by which the CDM may be applied to the unique structure of any genetic code. The mathematical relationship between the proportion of transitions at 4f degenerate nucleotide sites and the transition-to-transversion ratio is described. Predictions for five individual genetic codes, relative to the relationship between code structure and expected patterns of nucleotide substitution, are clearly defined. To test this "filter" hypothesis of genetic codes, simulated DNA sequence data sets were generated with a variety of input parameter values to estimate the relationship between patterns of nucleotide substitution and best-fit estimates of transition bias at 4f degenerate sites for both the universal genetic code and the vertebrate mitochondrial genetic code. These analyses confirm the prediction of the CDM that, all else being equal, even small differences in the structure of alternative genetic codes may result in significant shifts in the overall pattern of nucleotide substitution.     

Evolving new genetic codes

Although the genetic code is almost universal, natural variations exist that have caused evolutionary biologists to speculate about codon evolution. There are two predominant hypotheses that specify either a gradual (ambiguous intermediate) or stochastic (codon capture) change in the code. These hypotheses are similar to two biotechnology techniques that have been used to engineer the genetic code: a 'top down' approach, in which the whole organism is evolved for the ability to incorporate unnatural amino acids, and a 'bottom up' approach, in which aminoacyl-tRNA synthetases and their cognate tRNAs are engineered. The biotechnology experiments provide insights into natural codon evolution, and a combination of these approaches should enable the evolution of organisms that can incorporate unnatural amino acids throughout their proteomes.     

Some possible codes for encrypting data in DNA

Three codes are reported for storing written information in DNA. We refer to these codes as the Huffman code, the comma code and the alternating code. The Huffman code was devised using Huffman's algorithm for constructing economical codes. The comma code uses a single base to punctuate the message, creating an automatic reading frame and DNA which is obviously artificial. The alternating code comprises an alternating sequence of purines and pyrimidines, again creating DNA that is clearly artificial. The Huffman code would be useful for routine, short-term storage purposes, supposing – not unrealistically – that very fast methods for assembling and sequencing large pieces of DNA can be developed. The other two codes would be better suited to archiving data over long periods of time (hundreds to thousands of years).     

An Analysis of the Metabolic Theory of the Origin of the Genetic Code

A computer program was used to test Wong's coevolution theory of the genetic code. The codon correlations between the codons of biosynthetically related amino acids in the universal genetic code and in randomly generated genetic codes were compared. It was determined that many codon correlations are also present within random genetic codes and that among the random codes there are always several which have many more correlations than that found in the universal code. Although the number of correlations depends on the choice of biosynthetically related amino acids, the probability of choosing a random genetic code with the same or greater number of codon correlations as the universal genetic code was found to vary from 0.1% to 34% (with respect to a fairly complete listing of related amino acids). Thus, Wong's theory that the genetic code arose by coevolution with the biosynthetic pathways of amino acids, based on codon correlations between biosynthetically related amino acids, is statistical in nature. Received: 8 August 1996 / Accepted: 26 December 1996     

No accident: genetic codes freeze in error-correcting patterns of the standard genetic code

The standard genetic code poses a challenge in understanding the evolution of information processing at a fundamental level of biological organization. Genetic codes are generally coadapted with, or 'frozen' by, the protein-coding genes that they translate, and so cannot easily change by natural selection. Yet the standard code has a significantly non-random pattern that corrects common errors in the transmission of information in protein-coding genes. Because of the freezing effect and for other reasons, this pattern has been proposed not to be due to selection but rather to be incidental to other evolutionary forces or even entirely accidental. We present results from a deterministic population genetic model of code-message coevolution. We explicitly represent the freezing effect of genes on genetic codes and the perturbative effect of changes in genetic codes on genes. We incorporate characteristic patterns of mutation and translational error, namely, transition bias and positional asymmetry, respectively. Repeated selection over small successive changes produces genetic codes that are substantially, but not optimally, error correcting. In particular, our model reproduces the error-correcting patterns of the standard genetic code. Aspects of our model and results may be applicable to the general problem of adaptation to error in other natural information-processing systems.     

Yeast as a model organism for studying the evolution of non-standard genetic codes.

During the last 30 years, a number of alterations to the standard genetic code have been uncovered both in prokaryotes and eukaryotic nuclear and mitochondrial genomes. But, the study of the evolutionary pathways and molecular mechanisms of codon identity redefinition has been largely ignored due to the assumption that non-standard genetic codes can only evolve through neutral evolutionary mechanisms and that they have no functional significance. The recent discovery of a genetic code change in the genus Candida that evolved through an ambiguous messenger RNA decoding mechanism is bringing that naive assumption to an abrupt end by showing, in a rather dramatic way, that genetic code changes have profound physiological and evolutionary consequences for the species that redefine codon identity. In this paper, the recent data on the evolution of the Candida genetic code are reviewed and an experimental framework based on forced evolution, molecular genetics and comparative and functional genomics methodologies is put forward for the study of non-standard genetic codes and genetic code ambiguity in general. Additionally, the importance of using Saccharomyces cerevisiae as a model organism for elucidating the evolutionary pathway of the Candida and other genetic code changes is emphasised.     

Converting neural signals from place codes to rate codes

 The nervous system uses two basic types of formats for encoding information. The parameters of many sensory (and some premotor) signals are represented by the pattern of activity among an array of neurons each of which is optimally responsive to a different parameter value. This type of code is commonly referred to as a place code. Motor commands, in contrast, use rate coding: the desired force of a muscle is specified as a monotonic function of the aggregate rate of discharge across all of its motor neurons. Generating movements based on sensory information often requires converting signals from a place code to a rate code. In this paper I discuss three possible models for how the brain does this. Received: 24 July 2000 / Accepted in revised form: 2 February 2001     

Ensemble place codes in hippocampus: CA1, CA3, and dentate gyrus place cells have multiple place fields in large environments

Previously we reported that the hippocampus place code must be an ensemble code because place cells in the CA1 region of hippocampus have multiple place fields in a more natural, larger-than-standard enclosure with stairs that permitted movements in 3-D. Here, we further investigated the nature of hippocampal place codes by characterizing the spatial firing properties of place cells in the CA1, CA3, and dentate gyrus (DG) hippocampal subdivisions as rats foraged in a standard 76-cm cylinder as well as a larger-than-standard box (1.8 m×1.4 m) that did not have stairs or any internal structure to permit movements in 3-D. The rats were trained to forage continuously for 1 hour using computer-controlled food delivery. We confirmed that most place cells have single place fields in the standard cylinder and that the positional firing pattern remapped between the cylinder and the large enclosure. Importantly, place cells in the CA1, CA3 and DG areas all characteristically had multiple place fields that were irregularly spaced, as we had reported previously for CA1. We conclude that multiple place fields are a fundamental characteristic of hippocampal place cells that simplifies to a single field in sufficiently small spaces. An ensemble place code is compatible with these observations, which contradict any dedicated coding scheme.     

Circular codes revisited: a statistical approach

In 1996 Arquès and Michel [1996. A complementary circular code in the protein coding genes. J. Theor. Biol. 182, 45-58] discovered the existence of a common circular code in eukaryote and prokaryote genomes. Since then, circular code theory has provoked great interest and underwent a rapid development. In this paper we discuss some theoretical issues related to the synchronization properties of coding sequences and circular codes with particular emphasis on the problem of retrieval and maintenance of the reading frame. Motivated by the theoretical discussion, we adopt a rigorous statistical approach in order to try to answer different questions. First, we investigate the covering capability of the whole class of 216 self-complementary, C³ maximal codes with respect to a large set of coding sequences. The results indicate that, on average, the code proposed by Arquès and Michel has the best covering capability but, still, there exists a great variability among sequences. Second, we focus on such code and explore the role played by the proportion of the bases by means of a hierarchy of permutation tests. The results show the existence of a sort of optimization mechanism such that coding sequences are tailored as to maximize or minimize the coverage of circular codes on specific reading frames. Such optimization clearly relates the function of circular codes with reading frame synchronization.     

The organic codes. The basic mechanism of macroevolution.

The origin of the genetic code coincided with the origin of life, while the human codes of cultural evolution emerged almost four billion years later. Modern biology does not recognize any other organic code in nature, and is bound therefore to conclude that the whole of cellular evolution consisted of informational changes. Semantic transformations, natural conventions and biological meaning are things that officially do not exist in the organic world, and play no part in our reconstruction of development and evolution. And yet the properties of organic codes are beginning to emerge in various biological processes. Here it is shown that splicing, signal transduction and pattern formation can be accounted for precisely by the existence of organic codes. It is also shown that those processes were instrumental in bringing about major changes in the history of life, and it is concluded that every main step of macroevolution corresponded to the origin of a new organic code.     

Block structure and stability of the genetic code

It is known that different codons may be unified into larger groups related to the hierarchical structure, approximate hidden symmetries, and evolutionary origin of the universal genetic code. Using a simplified evolutionary motivated two-letter version of genetic code, the general principles of the most stable coding are discussed. By the complete enumeration in such a reduced code it is strictly proved that the maximum stability with respect to point mutations and shifts in the reading frame needs the fixation of the middle letters within codons in groups with different physico-chemical properties, thus, explaining a key feature of the universal genetic code. The translational stability of the genetic code is studied by the mapping of code onto de Bruijn graph providing both the compact visual representation of mutual relationships between different codons as well as between codons and protein coding DNA sequence and a powerful tool for the investigation of stability of protein coding. Then, the results are extended to four-letter codes. As is shown, the universal genetic code obeys mainly the principles of optimal coding. These results demonstrate the hierarchical character of optimization of universal genetic code with strictly optimal coding being evolved at the earliest stages of molecular evolution. Finally, the universal genetic code is compared with the other natural variants of genetic codes.     

Codes, operations, measurements and neural networks

Numerous neural codes and primary neural operations (logical and arithmetical ones, mappings, transformations) were listed [e.g. Perkel, D., Bullock, T.H., 1968. Neurosci. Res. Program Bull 6, 221-348] during the past decades. None of them is ubiquitous or universal. In reality neural operations take place in continuous time and working with unreliable elements, but they still can be simulated with synchronized discrete time scales and chaotic models. Here, a possible neural mechanism, called 'measure like' code is introduced and examined. The neurons are regarded as measuring devices, dealing with 'measures', more or less in mathematical sense. The subadditivity--eminent property of measures--may be implemented with neuronal refractoriness and such synapses operate like particle counters with dead time. This hypothetical code is neither ubiquitous, nor universal, e.g. temporal summation (multiplication) causes just the opposite phenomenon, the supra-additivity also with respect to the number of spikes (anti-measures). This is a cause of more difficult neural implementation of OR gate, than that of the AND. Possibilities for transitional mechanisms (e.g. between traditional logical gates, etc.) are stressed here. Parameter tuning might change either code or operation.     

Thirty years of multiple sequence codes

An overview is presented on the status of studies on multiple codes in genetic sequences. Indirectly, the existence of multiple codes is recognized in the form of several rediscoveries of Second Genetic Code that is different each time. A due credit is given to earlier seminal work related to the codes often neglected in literature. The latest developments in the field of chromatin code are discussed, as well as perspectives of single-base resolution studies of nucleosome positioning, including rotational setting of DNA on the surface of the histone octamers.     

The multiple codes of nucleotide sequences

Nucleotide sequences carry genetic information of many different kinds, not just instructions for protein synthesis (triplet code). Several codes of nucleotide sequences are discussed including: (1) the translation framing code, responsible for correct triplet counting by the ribosome during protein synthesis; (2) the chromatin code, which provides instructions on appropriate placement of nucleosomes along the DNA molecules and their spatial arrangement; (3) a putative loop code for single-stranded RNA-protein interactions. The codes are degenerate and corresponding messages are not only interspersed but actually overlap, so that some nucleotides belong to several messages simultaneously. Tandemly repeated sequences frequently considered as functionless “junk” are found to be grouped into certain classes of repeat unit lengths. This indicates some functional involvement of these sequences. A hypothesis is formulated according to which the tandem repeats are given the role of weak enhancer-silencers that modulate, in a copy number-dependent way, the expression of proximal genes. Fast amplification and elimination of the repeats provides an attractive mechanism of species adaptation to a rapidly changing environment.     

On the synthesis of DNA error correcting codes

DNA error correcting codes over the edit metric consist of embeddable markers for sequencing projects that are tolerant of sequencing errors. When a genetic library has multiple sources for its sequences, use of embedded markers permit tracking of sequence origin. This study compares different methods for synthesizing DNA error correcting codes. A new code-finding technique called the salmon algorithm is introduced and used to improve the size of best known codes in five difficult cases of the problem, including the most studied case: length six, distance three codes. An updated table of the best known code sizes with 36 improved values, resulting from three different algorithms, is presented. Mathematical background results for the problem from multiple sources are summarized. A discussion of practical details that arise in application, including biological design and decoding, is also given in this study.     

On the possibilities of error-detecting codes in nucleic acid molecules

Error-detecting codes have been known to mathematicians and to electrical engineers for over ten years. In general, such codes utilize an additional orparity bit for purposes of detecting errors by the addition of all positive binary bits or “1’s” occurring in any code word. However, since the process of addition is required for such code detection, it is not surprising that these codes have not been applied to the nucleic acid molecule. In 1962, P. I. Hershberg (Trans. I.R.E., CS-10, 280–4, 1962) outlined a categorical constraint which permitted the realization of a class of error-detecting codes which did not require parity bits. This class of codes is applied to the nucleic acid molecule in the present paper.