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The proteomic origin of the genetic code.

INTRODUCTION: The origin and evolution of the genetic code is a central problem in molecular biology. Classical models have emphasized stereochemistry, frozen accidents, or adaptive optimization, often treating proteins as passive products of preexisting codes. More recent views instead portray the code as a dynamic, coevolving system shaped by reciprocal interactions among amino acids, RNA, and early catalysts. AREAS COVERED: Here, I review efforts of phylogeny reconstruction of the history of tRNA, protein structural domains, and dipeptide sequences in proteomes. These complementary approaches allow exploration of the entry of amino acids and codons into the code, and the transition from an operational RNA code in the tRNA acceptor arm to the canonical code in the anticodon loop. Evidence for ancestral synthetase enzymes with dual functions in aminoacylation and peptide-bond formation, as well as early bidirectional (sense-antisense) coding reflected in dipeptide-antidipeptide emergence is also discussed. EXPERT OPINION: The genetic code is best viewed as a proteome-driven, evolvable system in which early peptides actively shaped coding rules by stabilizing structure, expanding chemical diversity, and enhancing catalysis. This perspective connects origin-of-life studies with modern efforts of code expansion, translational engineering, and peptide-based therapeutics, highlighting the impact of the code's proteomic origin.

Genetic Code↗

Molecular duality of DNA ligase in axolotl corresponds to distinctive transcriptional information.

Based upon the use of specific antibodies and sucrose gradient sedimentation analysis, the present work describes the use of the post-transcriptional equipment of the urodele egg to compare the information contained in two RNA samples extracted from respectively liver and activated axolotl eggs. It is shown that besides the normal DNA ligase activity present in the host Pleurodeles eggs, RNA can translate for the specific carried information revealing a difference between the two samples. Moreover, unlike in nuclear transplantation, the homologous DNA ligases are not mutually exclusive. These observations give a new convincing support of the genetic basis of the molecular duality of DNA ligases.

Ambystoma↗

Information Theory, Scaling Laws and the Thermodynamics of Evolution.

Renormalization symmetry and the Legendre transformation are imposed on a parametized form of ergodic source uncertainty, a widely-applied model for "languages" ranging from the spoken word to genetic codes. Using the Shannon-McMillan theorem to identify a duality between source uncertainty and free energy density, this procedure: (i) suggests that a punctuated "phase change" and resulting sudden fragmentation or coalescence should be the norm for "language"-based phenomena, particularly the transfer of "genetic" information within reproducing populations; (ii) gives a power law for that phase change near transition; (iii) provides a "disorder" construct similar to an entropy which may trigger higher degrees of punctuation in social systems than is suggested from simple physical analogs; and (iv) gives "equations of state" relating ensemble averages which should be observable within coalesced systems. The general formalism is explicitly applied to problems of speciation, coevolution and group selection, and comparison made with the work of Eigen and his associates.Copyright 1998 Academic Press Limited

Journal Article↗

T cell receptor alpha-, beta-, and gamma-genes in T cell and pre-B cell acute lymphoblastic leukemia.

We examined alpha-, beta-, and gamma-T cell receptor (TCR) gene activation within acute lymphoblastic leukemias (ALLs) that represent early stages of B and T cell development. We wished to determine if TCR rearrangement and expression was lineage restricted, showed any developmental hierarchy, or could identify new subsets of T cells. Rearrangement of gamma and beta TCR genes occurred early in development but in no set order, and most T-ALLs (22/26) were of sufficient maturity to have rearranged both genes. T-ALLs preferentially rearranged C gamma 2 versus the C gamma 1 complex; no preference within the beta locus was apparent. Once rearranged, the beta TCR continued to be expressed (11/13), whereas the gamma TCR was rarely expressed (3/14). The alpha TCR was expressed only in more mature T-ALLs (8/14) that usually displayed T3. The 3A-1 T cell associated antigen appeared earliest in development followed by T11 and T3. Within pre-B cell ALL a higher incidence of lineage spillover was noted for gamma TCR rearrangements (8/17) than for beta rearrangements (3/17). This also contrasts with the only occasional rearrangement of immunoglobulin (Ig) heavy chains (3/25) in T-ALL. However, in pre-B ALL the pattern of gamma TCR usage was distinct from that of T cells, with the C gamma 1 complex utilized more frequently. Almost all ALLs could be classified as pre-B or T cell in type by combining Ig and TCR genes with monoclonal antibodies recognizing surface antigens, although examples of lineage duality were noted. Unique subpopulations of cells were discovered including two genetically uncommitted ALLs that failed to rearrange either Ig or TCR loci. Moreover, two T lymphoblasts were identified that possessed the T3 molecule but failed to express alpha plus beta TCR genes. These T-ALLs may represent a fortuitous transformation of T cell subsets with alternative T3-Ti complexes.

B-Lymphocytes↗

Kinin receptors.

Rapid developments are expected in the molecular pharmacology of both B1, and B2 types of kinin receptors, since the underlying genetic structures are now known and widely studied. The consequences of kinin receptor duality and physiopathological regulation have not yet been fully appreciated. Medicinal chemistry is also an active front of research in kinin pharmacology, as more effective drugs targeted at kinin receptors are regularly reported. Various complementary molecular approaches (the receptor binding, cloning, immunoreacting, mutagenesis, inactivation, the study of regulation, allelic polymorphisms, and so forth) are expanding our knowledge of the role of kinins in allergy, inflammation, and singularly, renal medicine.

Amino Acid Sequence↗

Advances in medical genetics.

Although advances in medical genetics are designed ultimately to help human beings receive better health care, they pose many problems for society. Some of these concerns are real, but others result from misunderstanding and/or misrepresentation of the true implication of certain developments in genetics. It is obvious that the geneticist must play a dual role in society as scientist and as advocate. Although such a duality or role is not easy, it is not impossible. However, it does mean that the training of the medical geneticist must include more than exposure to the scientific approach.

Biomedical Research↗

Dual processes and an invariance result for exchangeable models in population genetics.

By means of a representation as interactive particle systems, dual processes are constructed for a large class of exchangeable models in population genetics. It is shown that as the population size becomes large these dual processes tend in distribution to a particularly tractable limiting dual process. Properties of the models are analyzed using the duality relationship and approximate expressions are obtained for various quantities. Diffusion approximations follow easily from the invariance result.

Animals↗

A duality in aging: the equivalence of mortality models based on radically different concepts.

Several alternative mortality models fit Swedish old-age mortality data equally well. The models build on two different concepts of the heterogeneity of individuals in a population. The first concept concerns fixed, genetic differences among individuals in their risk of death. The second concept involves acquired susceptibility to death due to physiological changes and environmental influences. We show that alternative mortality models based on either of these two concepts or some mix of them lead to the same parametric form of observed age-specific death rates. We discuss this duality property of mortality processes and show that even when a mortality model fits the data, the concepts used to construct the model may not be correct.

Adult↗

A genetic reconstruction of the history of the population of the Iberian Peninsula.

The genetic patterns detectable in human populations of the Iberian Peninsula are shown by means of 'synthetic genetic maps', i.e. geographic maps of the highest principal components (PC) of gene frequencies. This method of analysis separates independent patterns of the genetic landscape, which hopefully represents different, major evolutionary events of the past. Among these are clines established by ancient important migrations, and local differentiations of populations due to barriers responsible for relative isolation. Only events of some magnitude from a demographic point of view, involving populations having initially definite genetic differences are detectable by the method. For this to be true, the genetic consequences of these events must not have been entirely smoothed out by later, prolonged genetic exchange between neighbours; but simulations have shown that long clines produced by major migrations can be rather stable in time. The first synthetic map, corresponding to the first PC, shows that the major difference in the Iberian Peninsula is that between people originally of Basque and non-Basque descent. The recession in time of the boundaries of the Basque-speaking area seems correlated with the progressive genetic dilution of the Basque genotype in modern populations, as we move away from the centre of the Basque area. Clearly there must have been a close relationship in the progressive loss of the Basque language and increasing genetic admixture with neighbours. Most probably, Basques represent descendants of Paleolithic and/or Mesolithic populations and non-Basques later arrivals, beginning with the Neolithic. The second synthetic map is correlated with early Neolithic infiltrations from the eastern edge of the Pyrenees. It has been shown by archaeologists that, in some areas, early Neolithics lived side by side at overlapping dates with well developed Mesolithics. The demographic impact of Neolithic farmers versus Mesolithics, and therefore their genetic influence was thus less important in the Iberian Peninsula than in Central Europe. The third synthetic map shows a correlation with the linguistic and historical duality between the Atlantic and Mediterranean fringes, which developed in the first millennium B.C. and was probably determined, to some extent, by infiltrations through the Pyrenees of the Urnfield cultural elements as well as by several other later events.

Biological Evolution↗

The quality of medical science.

Is the quality of science aimed at understanding and treating disease inferior to more basic investigations of basic biology, or does the different quality of medical science reflect a distinct nature? This duality in the meaning of quality is central to any critique of the quality of medical science. The nature of medical science, which deals with the dysfunction of integrated genetic, epigenetic, environmental, or stochastic phenomenon, is distinct from that of basic science which seeks to describe discrete biological processes. In physical sciences it is generally accepted that there are practical boundaries between disciplines such as quantum physics, thermodynamics, and chemistry even though, in theory, such investigations are related. In meteorology, the development of chaos theory establishes that there are even theoretical limits to the ability to predict large scale processes from their essential, constituent processes. So too, the quality of medical science may be distinct from that of basic biology.

Attitude↗

Int-2: a member of the fibroblast growth factor family has different subcellular fates depending on the choice of initiation codon.

The int-2 gene, which encodes a member of the fibroblast growth factor family, was discovered as a protooncogene transcriptionally activated following proviral insertion into adjacent chromosomal DNA. Analyses of the synthesis and processing of the int-2 protein, using an SV40-based vector to express cloned cDNA, showed four major products in the size range 27.5-31.5 kd that were associated with the secretory pathway. Further experiments using a cell-free translation system programmed with int-2 cRNA revealed a larger N-terminally extended protein. Site-directed mutagenesis of possible initiation codons confirmed that the first in-frame AUG codon would specify the start of a protein that includes a signal peptide for transport into the endoplasmic reticulum. However, protein synthesis also initiates at an upstream CUG codon to yield a polypeptide extended at the N-terminus by 29 amino acids. Immunofluorescent staining showed that a substantial proportion of the CUG-initiated protein resides in the cell nucleus, while a truncated int-2, lacking both the N-terminal extension and the signal peptide, was exclusively nuclear. These observations suggest that a nuclear localisation signal occurs in the body of the int-2 molecule, but is only accessible to the nuclear transport system if entry to the secretory pathway is compromised. Thus, the choice of initiation codon changes the subcellular fate of the int-2 protein and provides the potential for a duality of function through alternative transport pathways.

Animals↗

From records to self-description: the role played by RNA in early evolutive systems.

We study the appearance of genetic information starting from a system where self-reproductive and enzymatic functions are supported by the same sort of molecules. In a first phase, the information must have arisen in the form of rate independent sequences as records of enzymatic functions. Although this stage must have played an important role in evolution, it will be shown how its evolutive capacities were blocked by the impossibility of appearance of geno/phenotype duality. Finally, a logical scheme is proposed for a transition process toward a system with a code offering a simplification of the conditions required from the assumption of a maximum use of the double RNA capacity, both reproductive and enzymatic.

Biological Evolution↗

The regulatory role of non-coding RNAs in taxane resistance of breast cancer.

Breast cancer remains a major health concern among women, characterized by a high risk and substantial mortality. Chemotherapy is widely employed as a standard treatment modality to eliminate malignant cells and improve patient survival. Nevertheless, recurrence and chemoresistance arising from taxane treatment have emerged as key factors driving the high mortality rates in cancer patients. Non-coding RNAs (ncRNAs), encompassing microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), represent a key functional output of the human genome and, via intricate regulatory networks, influence nearly all facets of cancer biology, including the development of chemoresistance. Importantly, in taxane-resistant breast cancer cells, the identified miRNAs displayed bifunctional roles: some promoted resistance, whereas others enhanced sensitivity. This functional duality is also observed in lncRNAs, highlighting their context‑dependent regulatory roles. Additionally, ncRNAs are enriched in taxane-resistant cells-derived exosomes, where they play a crucial role in spreading taxane resistance and chemotherapy failure through genetic modulation of taxane‑sensitive cells. Notably, targeting ncRNAs via various therapeutic approaches, including herbal compounds and synthetic peptides, has shown hopeful findings in reversing taxane resistance in breast cancer, highlighting a promising avenue for the management of taxane resistance in breast cancer.

Breast cancer↗

RAD51 is required for propagation of the germinal nucleus in Tetrahymena thermophila.

RAD51, the eukaryote homolog of the Escherichia coli recA recombinase, participates in homologous recombination during mitosis, meiosis, and in the repair of double-stranded DNA breaks. The Tetrahymena thermophila RAD51 gene was recently cloned, and the in vitro activities and induction of Rad51p following DNA damage were shown to be similar to that of RAD51 from other species. This study describes the pattern of Tetrahymena RAD51 expression during both the cell cycle and conjugation. Tetrahymena RAD51 mRNA abundance is elevated during macronuclear S phase during vegetative cell growth and with both meiotic prophase and new macronuclear development during conjugation. Gene disruption of the macronuclear RAD51 locus leads to severe abnormalities during both vegetative growth and conjugation. rad51 nulls divide slowly and incur rapid deterioration of their micronuclear chromosomes. Conjugation of two rad51 nulls leads to an arrest early during prezygotic development (meiosis I). We discuss the potential usefulness of the ciliates' characteristic nuclear duality for further analyses of the potentially unique roles of Tetrahymena RAD51.

Animals↗

The multifunctional TFIIH complex and transcriptional control.

RNA polymerase II (Pol II) requires seven general transcription factors (GTFs) and ATP for transcription initiation. Transcription factor IIH (TFIIH) has emerged as the sole GTF with enzymatic activity. In addition to its essential role in transcription initiation, recent studies have demonstrated a direct involvement of TFIIH in DNA excision repair processes. The enzymatic properties and functional duality of TFIIH make it a prime target for regulation by viral and cellular factors.

Amino Acid Sequence↗

Bacteriophage P1 Bof protein is an indirect positive effector of transcription of the phage bac-1 ban gene in some circumstances and a direct negative effector in other circumstances.

Previous genetic studies have suggested that the Bof protein of bacteriophage P1 can act as both a negative and a positive regulator of phage gene expression: in bof-1 prophages, the ref gene and a putative phage ssb gene are derepressed, but expression of an operator-semiconstitutive variant of the phage ban gene (bac-1) is markedly reduced. An explanation of this apparent duality is suggested by recent reports that Bof is a corepressor of genes that are regulated by the phage C1 repressor, including the autoregulated c1 gene itself. Here we show, by means of operon fusions to lacZ, that the balance points between Bof-mediated decreases in c1 expression and Bof-mediated increases in C1 efficacy are different among various C1-regulated genes. Thus, expression of Bof by P1 prophages affects some genes (e.g., bac-1 ban) positively, and others (e.g., ref) negatively. Even at bac-1 ban, where the positive indirect effect of Bof is physiologically dominant, Bof can be seen to act as a corepressor if C1 is supplied from a nonautoregulated (ptac-c1) source, eliminating the effect of Bof on C1 synthesis.

Bacteriophages↗

Replication of bacteriophage ribonucleic acid: some physical properties of single-stranded, double-stranded, and branched viral ribonucleic acid.

Replicative intermediate (RI) is considered to be the double-stranded ribo-nucleic acid (RNA) template for synthesis of viral RNA, with bound nascent single-stranded viral RNA. A theoretical description of RI is based on the analysis of a steady state of biopolymerization on a template which determines not only nucleotide sequence, but also chain length. The hydrodynamic properties of RI isolated from Escherichia coli infected with bacteriophage R17 are compared with those of RNA isolated from R17 (single-stranded RNA) and of replicative form (RF) isolated from E. coli infected with R17. RF is double-stranded RNA template without any single-stranded component. Whereas S for R17 RNA is a function of the ionic strength (Gamma/2) of the solvent, S is almost invariant with Gamma/2 for RF. By contrast S for RI lies between the sedimentation constants for R17 RNA and RF and S varies with Gamma/2 as does R17 RNA. The weight distribution of S for RI demonstrates the heterogeneity of this material, and the variation in the weight distribution with ionic strength demonstrates the duality of structure in RI. Using S and [eta], the Mw for RI is estimated to be 2.6 x 10(6) daltons, as compared with the theoretical value of 2.9 x 10(6) daltons.

Coliphages↗