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Genetic code development by stop codon takeover.

A novel theoretical consideration of the origin and evolution of the genetic code is presented. Code development is viewed from the perspective of simultaneously evolving codons, anticodons and amino acids. Early code structure was determined primarily by thermodynamic stability considerations, requiring simplicity in primordial codes. More advanced coding stages could arise as biological systems became more complex and precise in their replication. To be consistent with these ideas, a model is described in which codons become permanently associated with amino acids only when a codon-anticodon pairing is strong enough to permit rapid translation. Hence all codons are essentially chain-termination or "stop" codons until tRNA adaptors evolve having the ability to bind tightly to them. This view, which draws support from several lines of evidence, differs from the prevalent thinking on code evolution which holds that codons specifying newer amino acids were derived from codons encoding older amino acids.

Amino Acids

Consideration on the genetic code.

In this paper there are presented data and arguments which indicate that the genetic code also contains the information for the assembling of the trinucleotides and amino acids in the DNA-histones system, which works as an intra-cellar computer.

Genetic Code

A quantitative measure of error minimization in the genetic code.

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.

Amino Acids

[The tricarboxylic acid cycle and the genetic code].

Application of quantum--mechanical calculations of interaction energy of nitrous bases in DNA triplets to genetic code permits division of codons and pertinent amino acids into two groups. The first one corresponds to the upper energetic level 150-170 kJ/mole per base pair (per a triplet codon on the average). The second group corresponds to the low energetic level 88/92 kJ/mole per base pair. Comparing this grouping of amino acids with their incorporations into the cycle of tricarboxylic acids it turns out that the majority of amino acids of the first group are incorporated into the cycle via acetyl-KoA. Most amino acids of the second group are incorporated directly. It seems that the ways of amino acids introduction into the cycle of tricarboxylic acids are to a certain degree predetermined by energetic interactions of nitrous bases in the genetic codons.

Amino Acids

The genetic code and error transmission.

The amino acid substitutions resulting from single-base substitution in the natural genetic code have been compared with those resulting from single-base substitutions in computer-generated random codes. Considering the amino acid properties of molecular weight, polar requirement, number of dissociating groups, pK(1)', isoelectric point, and alpha-helix forming ability, it is concluded that, for the natural code, single-base substitution in the first position of the codon tends to result in the substitution of an amino acid more similar to the original amino acid than would be expected from a random code. In the natural code, the second position of the codon plays the largest role in determining the properties of the amino acid.

Amino Acid Sequence

Hemoglobin and the genetic code. Evolution of protection against somatic mutation.

One-half of the twenty amino acids of the genetic code are just one mutational step away from the chain-terminator codons UAA, UAG, and UGA. It is postulated that somatic mutation to terminator is a hazard to which the organism has and to respond by adjusting certain proteins in the direction of fewer mutable residues. This view is supported by calculations based on the primary structure of five of the human hemoglobin chains. Each chain is scored for mutability to terminator in accord with the numbers and kinds of amino acids present. Among the adult chains, the most essential one, the alpha, has lowest mutability. The beta and delta follow, and in order of the presumed harm to the organism of a shortage of chain copies. Ante-natal chains tend to have higher mutabilities, supporting the view that cumulative mutational change in DNA can do little if the gene ceases to transcribe early in life. Two other predicitons based on the supposition of effective selection against mutability to terminator are also met: chain length of polypeptides is negatively correlated with their scores for mutability to terminator, and examination of the recently determined sequence of beta messenger RNA shows preferential use of codons that are not readily mutable to terminator.

Amino Acid Sequence

An unusual genetic code in nuclear genes of Tetrahymena.

We have cloned and partially sequenced two histone H3 genes of Tetrahymena thermophila. The DNA sequences strongly suggest that both genes are active in the vegetatively growing cell. Comparison of the derived amino acid sequences of these two genes with the actual sequence of Tetrahymena histone H3 results in the surprising conclusion that TAA codes for glutamine. This represents the first demonstration of a coding function for this termination codon of the "universal" code. This observation has important implications for the evolution of ciliates and of the genetic code.

Amino Acid Sequence

Periodical changes of amino acid reactivity within the genetic code.

Enthalpies (delta H++) and entropies (delta S++) of activation for the reaction of 18 N'-hydroxysuccinimide esters of N-protected proteinaceous amino acids with p-anisidine were measured and free enthalpies of activation (delta G++) at 25 degrees C were calculated on this basis. A regular correlation between delta G++s and the corresponding amino acid codons was found. To obtain this correlation all the codons had to be arranged in a closed ring in which the consecutive codons were connected by one-step mutational changes. One-step mutations appeared as a regular series: 2,3,3,3,1,3,3,3,1,3,3,3,1,3,3,3,2,3,3,3. (the numbers denote a codon position in which a change took place). There were three such 'one-step mutation periods' in the ring, each containing 20 codons (in each block of 16 codons with A, U and C, in the central position and 4 codons containing G in the central position). The end of the third period (UG) and the beginning of the first period were bridged by the four codons of glycine with G in the second position. The values of delta G++ change similarly in each period, increasing upon approaching Lys, Pro, and Ile. The periodical relation between the chemical reactivities of the coded amino acids (reflected by delta G++s) and the structure of their codons could be of importance for the origin of the genetic code i.e. for selection of proper codons for the definite amino acids.

Amino Acid Sequence

Origin of the genetic code: a testable hypothesis based on tRNA structure, sequence, and kinetic proofreading.

We hypothesize that the origin of the genetic code is associated with the structure of the tRNA that existed in primal cells. The sequences of modern tRNA contain correlations which can be understood as "fossil" evidence of the secondary structure of primal tRNA. Kinetic proofreading through diffusion can amplify a low level of intrinsic selectivity of tRNA for its amino acid. Experimental tests of the theory are suggested.

Amino Acyl-tRNA Synthetases