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Codon-specific incorporation of noncoded amino acids into proteins can diversify the genetic code. Now, in both E. coli and S. cerevisiae, iterative rounds of selection can be used to isolate aminoacyl-tRNA synthetases that aminoacylate suppressor tRNAs with noncoded amino acids.
We have calculated the average effect of changing a codon by a single base for all possible single-base changes in the genetic code and for changes in the first, second, and third codon positions separately. Such values were calculated for an amino acid's polar requirement, hydropathy, molecular volume, and isoelectric point. For each attribute the average effect of single-base changes was also calculated for a large number of randomly generated codes that retained the same level of redundancy as the natural code. Amino acids whose codons differed by a single base in the first and third codon positions were very similar with respect to polar requirement and hydropathy. The major differences between amino acids were specified by the second codon position. Codons with U in the second position are hydrophobic, whereas most codons with A in the second position are hydrophilic. This accounts for the observation of complementary hydropathy. Single-base changes in the natural code had a smaller average effect on polar requirement than all but 0.02% of random codes. This result is most easily explained by selection to minimize deleterious effects of translation errors during the early evolution of the code.
The sequence of a representative mitochondrial gene COXI, encoding cytochrome c oxidase subunit I, was determined in five species that cover all the orders of the Prymnesiophyta with the exception of the Pavlovales. Through this analysis, we noticed that the 'stop' codon UGA appears frequently and, specifically, at conserved tryptophan (Trp) sites of the gene. We showed these sites were not edited in the corresponding mRNA in one of these species, Isochrysis galbana. Therefore, it is most likely that the UGA codon is used for Trp, and not as a stop codon, in prymnesiophytes. All the analyzed prymnesiophytes made a tight cluster on the COXI phylogenetic tree which includes representative species of green-algae, land plants, yellow-green algae, eustigmatophytes and a red-alga. This suggests a monophyletic origin for the prymnesiophytes. The same deviant genetic code, i.e. UGA for Trp, has also been found in the red-alga, Chondrus crispus. In spite of the fact that this red-alga and the prymnesiophytes, share the same deviant genetic code for Trp, close affinity between the two groups was not statistically supported by the phylogenetic analysis of COXI sequences.
Comparative path lengths in amino acid biosynthesis and other molecular indicators of the timing of codon assignment were examined to reconstruct the main stages of code evolution. The codon tree obtained was rooted in the 4 N-fixing amino acids (Asp, Glu, Asn, Gln) and 16 triplets of the NAN set. This small, locally phased (commaless) code evidently arose from ambiguous translation on a poly(A) collector strand, in a surface reaction network. Copolymerisation of these amino acids yields polyanionic peptide chains, which could anchor uncharged amide residues to a positively charged mineral surface. From RNA virus structure and replication in vitro, the first genes seemed to be RNA segments spliced into tRNA. Expansion of the code reduced the risk of mutation to an unreadable codon. This step was conditional on initiation at the 5'-codon of a translated sequence. Incorporation of increasingly hydrophobic amino acids accompanied expansion. As codons of the NUN set were assigned most slowly, they received the most nonpolar amino acids. The origin of ferredoxin and Gln synthetase was traced to mid-expansion phase. Surface metabolism ceased by the end of code expansion, as cells bounded by a proteo-phospholipid membrane, with a protoATPase, had emerged. Incorporation of positively charged and aromatic amino acids followed. They entered the post-expansion code by codon capture. Synthesis of efficient enzymes with acid-base catalysis was then possible. Both types of aminoacyl-tRNA synthetases were attributed to this stage. tRNA sequence diversity and error rates in RNA replication indicate the code evolved within 20 million yr in the preIsuan era. These findings on the genetic code provide empirical evidence, from a contemporaneous source, that a surface reaction network, centred on C-fixing autocatalytic cycles, rapidly led to cellular life on Earth.
A better definition of the structural and thermodynamic determinants of the interaction of nucleic acids with proteins is shedding light on the origin of the genetic code, protein synthesis, and nucleic acid replication. This is also allowing to show a consistent biochemical framework for the appearance of these fundamental synthetic mechanisms. This article reviews recent significant developments in the field, and discusses an integrated model for a biochemically plausible evolution of these fundamental mechanisms of synthesis. This model is based on sequence-specific interactions between abiotically synthesized polynucleotides and polypeptides, and can account for a coordinate evolution of the genetic code, protein synthesis, and nucleic acid replication in living cells.
Simple procedures are proposed to quantify how much an effective property embodied in a given ranking of the twenty amino acids can be affected by random point mutations at nucleotide bases. As expected, of the various orderings tested, rankings based on most hydrophobicity scales exhibit low scores, thus offering better immunity towards such single-base mutations. This, however, occurs to different extents and the method allows sharp discriminations between the scales. Hydrophobicity scales based on global properties such as spatial environment data of proteins residues, or mutation matrices of amino acid replacements, generally behave better than those based on pure physicochemical properties of isolated residues. An averaged scale built from the available hydrophobicity scales exhibits one of the most favorable scores. A systematic search for the best amino acid order has been carried out across all possible scales. Optimized scales are characterized by the existence of a clustering scheme into three zones, within which permutations are more or less tolerated, depending on the zone and on the summation procedure used in the score calculation. The first cluster corresponds to the hydrophobic side, and includes the ten amino acids WMCFILVGRS. Next follows the ATP triad. The third cluster coincides with the hydrophilic side and includes, in the last seven positions, the amino acids EDKNQHY. Interpretation of these optimized scales in terms of codon positions in the genetic code further suggests a clustering scheme composed of four groups, WMCFILV-GRS-ATP-EDKNQHY, emphasizing the role of the second base as the main driving parameter. As a consequence, the conserved character of the genetic code is better reflected when it is displayed in UGCA ordering rather than in the commonly used UCAG ordering. The present a priori classification of the amino acids could find potential use in protein sequence homology and structure prediction.
Distances between amino acids were derived from the polar requirement measure of amino acid polarity and Benner and co-workers' (1994) 74-100 PAM matrix. These distances were used to examine the average effects of amino acid substitutions due to single-base errors in the standard genetic code and equally degenerate randomized variants of the standard code. Second-position transitions conserved all distances on average, an order of magnitude more than did second-position transversions. In contrast, first-position transitions and transversions were about equally conservative. In comparison with randomized codes, second-position transitions in the standard code significantly conserved mean square differences in polar requirement and mean Benner matrix-based distances, but mean absolute value differences in polar requirement were not significantly conserved. The discrepancy suggests that these commonly used distance measures may be insufficient for strict hypothesis testing without more information. The translational consequences of single-base errors were then examined in different codon contexts, and similarities between these contexts explored with a hierarchical cluster analysis. In one cluster of codon contexts corresponding to the RNY and GNR codons, second-position transversions between C and G and transitions between C and U were most conservative of both polar requirement and the matrix-based distance. In another cluster of codon contexts, second-position transitions between A and G were most conservative. Despite the claims of previous authors to the contrary, it is shown theoretically that the standard code may have been shaped by position-invariant forces such as mutation and base content. These forces may have left heterogeneous signatures in the code because of differences in translational fidelity by codon position. A scenario for the origin of the code is presented wherein selection for error minimization could have occurred multiple times in disjoint parts of the code through a phyletic process of competition between lineages. This process permits error minimization without the disruption of previously useful messages, and does not predict that the code is optimally error-minimizing with respect to modern error. Instead, the code may be a record of genetic process and patterns of mutation before the radiation of modern organisms and organelles.
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In an effort to develop an unnatural base pair with which to expand the genetic code we have examined a wide variety of simple phenyl rings derivatized with methyl, fluoro, or nitrogen. The small aromatic surface of these base pairs should prevent inter-strand intercalation, which is thought to inhibit the polymerase-mediated synthesis of base pairs with larger aromatic surface area. Surprisingly, despite reduced aromatic surface area and hydrogen-bonding potential, some of these base pairs are stable and synthesized with reasonable efficiency. We have also been examining the use of activity-based selection systems to evolve DNA polymerases to more efficiently recognize the unnatural substrates, and our initial successes are described.
In studies with A protein mutants of the tryptophan synthetase of Escherichia coli, missense supressors have been used to select for codon changes and corresponding amino acid replacements that are normally unobservable. The technique has permitted the detection of additional amino acid replacements expected on the basis of the genetic code.
Methods of k-neighbours and neural networks were used for prediction of pharmacological effects of new compounds wits tuftsin-like activities. The tested compounds were constructed by the complementarity rule of genetic code algorithm. Five of seven substitutions with stereocomplement amino acids in the tuftsin sequence lead to new active compounds. Thus, the use of amino acid complementary code can be a helpful tool for the construction of a new immunomodulating peptide.