The triplet genetic code had a doublet predecessor

Information theoretic analysis of genetic languages indicates that the naturally occurring 20 amino acids and the triplet genetic code arose by duplication of 10 amino acids of class-II and a doublet genetic code having codons NNY and anticodons GNN. Evidence for this scenario is presented based on the properties of aminoacyl-tRNA synthetases, amino acids and nucleotide bases.     

On the 28-gon symmetry inherent in the genetic code intertwined with aminoacyl-tRNA synthetases—The Lucas series

Despite considerable efforts it has remained unclear what principle governs the selection of the 20 canonical amino acids in the genetic code. Based on a previous study of the 28-gonal and rotational symmetric arrangement of the 20 amino acids in the genetic code, new analyses of the organization of the genetic code system together with their intrinsic relation to the two classes of aminoacyl-tRNA synthetases are reported in this work. A close inspection revealed how the enzymes and the 20 gene-encoded amino acids are intertwined on the polyhedron model. Complementary and cooperative symmetries between class I and class II aminoacyl-tRNA synthetases displayed by a 28-gon organization are discussed, and we found that the two previously suggested evolutionary axes within the genetic code overlap the symmetry axes within the two classes of aminoacyl-tRNA synthetases. Moreover, it has been shown that the side-chain carbon-atom numbers (2, 1, 3, 4 and 7) in the overwhelming majority of the amino acids recognized by each of the two classes of aminoacyl-tRNA synthetases are determined by a mathematical relationship, the Lucas series. A stepwise co-evolutionary selection logic of the amino acids is manifested by the amino acid side-chain carbon-atom number balance at ‘17’, when grouping the genetic code doublets in the 28-gon organization. The number ‘17’ equals the sum of the initial five numbers in the Lucas series, which are 2, 1, 3, 4 and 7.     

A Novel Theory on the Origin of the Genetic Code: A GNC-SNS Hypothesis

We have previously proposed an SNS hypothesis on the origin of the genetic code (Ikehara and Yoshida 1998). The hypothesis predicts that the universal genetic code originated from the SNS code composed of 16 codons and 10 amino acids (S and N mean G or C and either of four bases, respectively). But, it must have been very difficult to create the SNS code at one stroke in the beginning. Therefore, we searched for a simpler code than the SNS code, which could still encode water-soluble globular proteins with appropriate three-dimensional structures at a high probability using four conditions for globular protein formation (hydropathy, α-helix, β-sheet, and β-turn formations). Four amino acids (Gly [G], Ala [A], Asp [D], and Val [V]) encoded by the GNC code satisfied the four structural conditions well, but other codes in rows and columns in the universal genetic code table do not, except for the GNG code, a slightly modified form of the GNC code. Three three-amino acid systems ([D], Leu and Tyr; [D], Tyr and Met; Glu, Pro and Ile) also satisfied the above four conditions. But, some amino acids in the three systems are far more complex than those encoded by the GNC code. In addition, the amino acids in the three-amino acid systems are scattered in the universal genetic code table. Thus, we concluded that the universal genetic code originated not from a three-amino acid system but from a four-amino acid system, the GNC code encoding [GADV]-proteins, as the most primitive genetic code. Received: 11 June 2001 / Accepted: 11 October 2001     

Evolution of the mitochondrial genetic code I. Origin of AGR serine and stop codons in metazoan mitochondria

Summary AGA and AGG (AGR) are arginine codons in the universal genetic code. These codons are read as serine or are used as stop codons in metazoan mitochondria. The arginine residues coded by AGR in yeast orTrypanosoma are coded by arginine CGN throughout metazoan mitochondria. AGR serine sites in metazoan mitochondria are occupied mainly in corresponding sites in yeast orTrypanosoma mitochondria by UCN serine, AGY serine, or codons for amino acids other than serine or arginine. Based on these observations, we propose the following evolutionary events. AGR codons became unassigned because of deletion of tRNA Arg (UCU) and elimination of AGR codons by conversion to CGN arginine codons. Upon acquisition by serine tRNA of pairing ability with AGR codons, some codons for amino acids other than arginine mutated to AGR, and were caputed by anticodon GCU in serine tRNA. During vertebrate mitochondrial evolution, AGR stop codons presumably were created from UAG stop by deletion of the first nucleotide U and by use of R as the third nucleotide that had existed next to the ancestral UAG stop.     

Speculations on the evolution of the genetic code

An evolutionary scheme is postulated in which the bases enter the genetic code in a definite temporal sequence and the correlated amino acids are assigned definite functions in the evolving system.The scheme requires a singlet code (guanine coding for glycine) evolving into a doublet code (guanine-cytosine doublet coding for gly (GG), ala (GC), arg (CG), pro (CC)). The doublet code evolves into a triplet code. Polymerization of nucleotides is thought to have been by block polymerization rather than by a template mechanism. The proteins formed at first were simple structural peptides. No direct nucleotide-amino acid stereo-chemical interaction was required. Rather an adaptor-type indirect mechanism is thought to have been functioning since the origin.     

Speculations on the evolution of the genetic code.

An evolutionary scheme is postulated in which the bases enter the genetic code in a definite temporal sequence and the correlated amino acids are assigned definite functions in the evolving system. The scheme requires a singlet code (guanine coding for glycine) evolving into a doublet code (guanine-cytosine doublet coding for gly (GG), ala (GC), arg (CG), pro (CC). The doublet code evolves into a triplet code. Polymerization of nucleotides is thought to have been by block polymerization rather than by a template mechanism. The proteins formed at first were simple structural peptides. No direct nucleotide-amino acid stereo-chemical interaction was required. Rather an adaptor-type indirect mechanism is thought to have been functioning since the origin.     

Engineering Translation Components for Genetic Code Expansion

The expansion of the genetic code consisting of four bases and 20 amino acids into diverse building blocks has been an exciting topic in synthetic biology. Many biochemical components are involved in gene expression; therefore, adding a new component to the genetic code requires engineering many other components that interact with it. Genetic code expansion has advanced significantly for the last two decades with the engineering of several components involved in protein synthesis. These components include tRNA/aminoacyl-tRNA synthetase, new codons, ribosomes, and elongation factor Tu. In addition, biosynthesis and enhanced uptake of non-canonical amino acids have been attempted and have made meaningful progress. This review discusses the efforts to engineer these translation components, to improve the genetic code expansion technology.     

线粒体遗传密码及基因组遗传密码的对称分析

病毒、细菌和真核生物的氨基酸编码都使用相同的遗传密码,表明它们可能有共同的来源。但人和牛的线粒体的遗传密码和基因组的遗传密码相比,出现以下不同;（1）ATA编码甲硫氮酸M而不是异亮氨酸I。（2）TGA不再是终止密码子X而编码色氨酸W。（3）AGA和AGG不再是精氨酸R的密码子而变为终止密码子X。应用高维空间拓扑分析的方法,对线粒体遗传密码和基因组遗传密码的6维编码空间进行对称性分析,得到如下结果：（1）线粒体遗传密码的起始密码子是2个而不是1个。（2）线粒体遗传密码的终止密码子是4个而不是3个。（3）线粒体遗传密码空间只有2、4、6三种偶数简并度而没1、3两种奇数简并度,表明其对称度较高。（4）线粒体遗传密码空间除丝氨酸S分成两个平行的子空间之外,终止密码子X亦分成两个平行的子空间,表明其连通度较低。（5）线粒体遗传密码一基因组遗传密码相比,共有3个简并平面出现变异,即：1001λλ（M和I）,011λ1λ（W和X）,以及1011λλ（S和X或S和R）。（6）基因组遗传密码的1、3两种奇数简并度可能来源于线粒体遗传密码的1001λλ平面和011λ1λ平面的对称性破缺。对线粒体遗传密码变异的生物学意义及遗传密码的起源进行了分析和讨论。     

Unambiguous correspondence and complementarity of the chemical properties of amino acids and anticodons of the genetic code

The chemical language of genetic code is proposed. As a result of chemical language application for the analysis of the modern genetic code, the existence of an unambiguous correspondence between the chemical properties of amino acids and their coding triplets (codons and anticodons) is shown. This confirms the hypothesis of the code chemical determination. The complementarity between the chemical properties of amino acids and their anticodons (but not the codons) has been found also to exist. This observation supports the hypothesis of the genetic code determination by the direct recognition and also underlines the primary role of anticodon in the origin of genetic code in comparison with codons.     

A working hypothesis on the interdependent genesis of nucleotide bases,protein amino acids,and primitive genetic code

In the course of experimental approach to the chemical evolution in the primeval sea, we have found that the main products from formaldehyde and hydroxylamine are glycine, alanine, serine, aspartic acid etc., and the products from glycine and formaldehyde are serine and aspartic acid. Guanine is found in the two-letter genetic codons of all these amino acids.Based upon the finding and taking into consideration the probable synthetic pathways of nucleotide bases and protein amino acids in the course of chemical evolution and a correlation between the two-letter codons and the number of carbon atoms in the carbon skeleton of amino acids, 1 have been led to a working hypothesis on the interdependent genesis of nucleotide bases, protein amino acids, and primitive genetic code as shown in Table I.Protein amino acids can be classified into two groups: Purine Group amino acids and Pyrimidine Group amino acids. Purine bases and Pyrimidine bases are predominant in two-letter codons of amino acids belonging to the former and the latter group respectively.Guanine, adenine, and amino acids of the Purine Group may be regarded as synthesized from C₁ and C₂ compounds and N₁ compounds (including C₁N₁ compunds such as HCN), probably through glycine, in the early stage of chemical evolution.Uracil, cytosine, and amino acids of the Pyrimidine Group may be regarded as synthesized directly or indirectly from three-carbon chain compounds. This synthesis became possible after the accumulation of three-carbon chain compounds and their derivatives in the primeval sea.The Purine Group can be further classified into a Guanine or (Gly+nC₁) Subgroup and an Adenine or (Gly+nC₂) Subgroup or simply nC₂ Subgroup. The Pyrimidine Group can be further classified into a Uracil or C₃C₆C₉ Subgroup and a Cytosine or C₅-chain Subgroup (Table I).It is suggested that the primitive genetic code was established by a specific interaction between amino acids and their respective nucleotide bases. The interaction was dependent upon their concentration in the primeval environments and the binding constants between amino acids and their respective bases.Presented at the International Symposium (Lipmann Symposium) on The Concepts of Chemical Recognition in Biology held in Grignon near Versailles (France) on July 18–20, 1979.     

A theory of the origin of life

Life on Earth is essentially nucleic acids (NAs) influencing peptide synthesis such that NA replication is favored. It is proposed that the ability to synthesize polypeptides evolved gradually — one peptide bond at a time. The proposed evolution of the peptide synthesis apparatus begins with a transfer NA (tNA) which catalyzes the transfer of activated amino acids to accessible amino groups in its environment. The resulting capped molecules (with single amino acid caps) in turn favor NA replication. The proposed evolution of the peptide synthesis apparatus from the tNA onward is characterized by a progressive increase in the number of amino acids per cap: two tNAs jointly produce a dipeptide cap, three tNAs jointly produce a tripeptide cap, etc. Messenger NAs evolve because they can specify the composition and sequence order of the peptide caps. Lastly, ribosomal NAs evolve. The origin, expansion, and standardization of the genetic code are discussed. It is proposed that the present triplet code evolved by a process of codon length refinement, and that originally codons of varying lengths were allowable, as were unassigned bases between codons. An environmental supply of activated compounds for early evolving entities is proposed. An environmental NA replication process via single template-directed bond formation events is proposed. An environmental retention and redistribution process is proposed to have acted as a functional substitute for the cell wall and cell division of early evolving entities.     

A unifying concept for the amino acid code

The structure of the genetic code is related to a Gray code, which is a plausible theoretical model for an amino acid code. The proposed model implies that the most important factor in shaping the code was the effects of mistakes in translation, not effects of mutations. Another possible implication is that the preservation of stiffness and flexibility at appropriate places in a protein chain is as important in protein structure as the appropriate placement of hydrophilic (external) and hydrophobic (internal) residues. Other results are a simple conceptualization of the relationships among the 20 amino acids and their relations to their codons. The detailed relationships are summarized in the following ‘similarity alphabet’: ala, thr, gly, pro, ser; asp, asn, glu, gln, lys; his, arg, trp, tyr, phe; leu, met, ile, val, cys; (ATGPS DNEQK HRWYF LMIVC in the one-letter code). This alphabet falls into four groups of amino acids: small, external, large, internal. The approximate relation of the groups to their codons is expressed as: the first base of a codon controls size—a purine means a small amino acid, a pyrimidine means large; the middle base controls cloisterednes—purine means external, pyrimidine means internal. These relationships express the minimum change principle upon which the code appears to be founded.     

Structuring of the genetic code took place at acidic pH

I have observed that in multiple regression the number of codons specifying amino acids in the genetic code is positively correlated with the isoelectric point of amino acids and their molecular weight. Therefore basic amino acids are, on average, codified in the genetic code by a larger number of codons, which seems to imply that the genetic code originated in an acidic 'intracellular' environment. Moreover, I compare the proteins from Picrophilus torridus and Thermoplasma volcanium, which have different intracellular pH and I define the ranks of acidophily for the amino acids. A simple index of acidophily (AI), which can be easily obtained from acidophily ranks, can be associated to any protein and, therefore, can also be associated to the genetic code if the number of synonymous codons attributed to the amino acids in the code is assumed to be the frequency with which the amino acids appeared in ancestral proteins. Finally, the sampling of the variable AI among organisms having an intracellular pH less than or equal to 6.6 and those having a non-acidic intracellular pH leads to the conclusion that the value of the genetic code's AI is not typical of proteins of the latter organisms. As the genetic code's AI value is also statistically not different from that of proteins of the organisms having an acidic intracellular pH, this supports the hypothesis that the structuring of the genetic code took place in acidic pH conditions.     

简并性还是多态性?——遗传密码子设定的进化特点的剖析(英文)

遗传密码子的设定表现出令人困惑的多态性特点 :不同氨基酸拥有的密码子的数目 ,除 5个外 ,从 1个到 6个都有 .这种特点显示出密码子无论在翻译行为还是进化轨迹上 ,都存在诸多的异质性 .因此 ,简并性一词的收敛含义 ,并不能表征这种多态性的进化内涵 .没有同义密码子的AUG(Met)和UGG (Trp)并无简并现象 .其余的密码子则可分为两大类 :一类是 ,4个同义密码子为 1组 ,具有相同的第 1、2位碱基 ,并遵循“3中读 2”的读出规则 .同组的 4个同义密码子 ,不过是来自同一个双字母原始密码子 (XYN)的孑遗物 ,从这个意义上讲 ,也不宜视为简并现象 ;另一类则主要是 ,2个同义密码子为一组 ,并遵循“3中读 3”读出规则 .它们是由编码 2个氨基酸的双义原始密码子 ,第 3位的未定碱基N进一步设定形成 .至于有 6个同义密码子的 ,特别令人困感不解的组别 ,实际上是 4 + 2个 ,这启示它们可能源于上述两大类 .遗传密码子多态性的起源 ,可能始于最初阶段 ,氨基酸同某类寡核苷酸的起始二联体的相互作用 ,而完成于所有的双义原始密码子的第 3位碱基的分化 .这种进化轨迹被传统的简并性一词所模糊 ,并导致鉴定各有关理论可信性的坚实依据和令不同观点取得共识的基础被掩盖起来 .这可能就是在遗传密码子起源领域里 ,长期存在着众     

Origins of gene, genetic code, protein and life: comprehensive view of life systems from a GNC-SNS primitive genetic code hypothesis

We have investigated the origin of genes, the genetic code, proteins and life using six indices (hydropathy, α-helix, β-sheet and β-turn formabilities, acidic amino acid content and basic amino acid content) necessary for appropriate three-dimensional structure formation of globular proteins. From the analysis of microbial genes, we have concluded that newly-born genes are products of nonstop frames (NSF) on antisense strands of microbial GC-rich genes [GC-NSF(a)] and from SNS repeating sequences [(SNS)_n] similar to the GC-NSF(a) (S and N mean G or C and either of four bases, respectively). We have also proposed that the universal genetic code used by most organisms on the earth presently could be derived from a GNC-SNS primitive genetic code. We have further presented the [GADV]-protein world hypothesis of the origin of life as well as a hypothesis of protein production, suggesting that proteins were originally produced by random peptide formation of amino acids restricted in specific amino acid compositions termed as GNC-, SNS and GC-NSF(a)-0th order structures of proteins. The [GADV]-protein world hypothesis is primarily derived from the GNC-primitive genetic code hypothesis. It is also expected that basic properties of extant genes and proteins could be revealed by considerations based on the scenario with four stages This review is a modified English version of the paper, which was written in Japanese and published inViva Origino 2001 29 66–85.     

A New Classification Scheme of the Genetic Code

Since the early days of the discovery of the genetic code nonrandom patterns have been searched for in the code in the hope of providing information about its origin and early evolution. Here we present a new classification scheme of the genetic code that is based on a binary representation of the purines and pyrimidines. This scheme reveals known patterns more clearly than the common one, for instance, the classification of strong, mixed, and weak codons as well as the ordering of codon families. Furthermore, new patterns have been found that have not been described before: Nearly all quantitative amino acid properties, such as Woeses polarity and the specific volume, show a perfect correlation to Lagerkvists codon–anticodon binding strength. Our new scheme leads to new ideas about the evolution of the genetic code. It is hypothesized that it started with a binary doublet code and developed via a quaternary doublet code into the contemporary triplet code. Furthermore, arguments are presented against suggestions that a simpler code, where only the midbase was informational, was at the origin of the genetic code.     

Rook’s tour representation of the genetic code

Disconnected recurrences of the stop signal, serine and arginine appear in the original representation of the genetic code, and of the stop signal, arginine, serine and leucine in the codon ring representation. To achieve connectedness along with structural continuity, arook’s tour representation is presented here. On the basis of structural similarities and disparities in their side groups, each of the 20 amino acids is associated with a domain comprised of from one to six contiguous squares on the chess board. As the rook moves on the chess board, it reaches all 64 squares in the ordering of the codon numbers, which prescribe the codons by a simple formula based on the position and size of the nucleotides in a triplet. Recurrences of the stop signal, arginine and serine occur naturally on the tour as the rook enters each of the latter domains for the second time. A mathematical equivalent of the rook’s tour may enter as a programming device in the implementation of the code by the RNAs.     

Characterization of the N-linked high-mannose oligosaccharides of the insulin pro-receptor and mature insulin receptor subunits.

An interesting pattern in the genetic code was reported previously [Blalock & Smith (1984) Biochem. Biophys. Res. Commun. 121, 203-207]. In the 5'-to-3' direction, codons for hydrophilic and hydrophobic amino acids are generally complemented by codons for hydrophobic and hydrophilic amino acids respectively. The average tendency of codons for 'unchanged' (slightly hydrophilic) amino acids was to be complemented by codons for 'unchanged' amino acids. We now show that the same pattern results when the complementary codon is read in the 3'-to-5' direction. This pattern is further shown to result in the interaction of peptides specified by complementary RNAs regardless of whether the amino acids are assigned in the 5'-to-3' or the 3'-to-5' direction. Here we demonstrate that peptides specified by complementary RNAs bind to each other with specificity and high affinity.     

Evolution of the Genetic Code by Incorporation of Amino Acids that Improved or Changed Protein Function

Fifty years have passed since the genetic code was deciphered, but how the genetic code came into being has not been satisfactorily addressed. It is now widely accepted that the earliest genetic code did not encode all 20 amino acids found in the universal genetic code as some amino acids have complex biosynthetic pathways and likely were not available from the environment. Therefore, the genetic code evolved as pathways for synthesis of new amino acids became available. One hypothesis proposes that early in the evolution of the genetic code four amino acids—valine, alanine, aspartic acid, and glycine—were coded by GNC codons (N = any base) with the remaining codons being nonsense codons. The other sixteen amino acids were subsequently added to the genetic code by changing nonsense codons into sense codons for these amino acids. Improvement in protein function is presumed to be the driving force behind the evolution of the code, but how improved function was achieved by adding amino acids has not been examined. Based on an analysis of amino acid function in proteins, an evolutionary mechanism for expansion of the genetic code is described in which individual coded amino acids were replaced by new amino acids that used nonsense codons differing by one base change from the sense codons previously used. The improved or altered protein function afforded by the changes in amino acid function provided the selective advantage underlying the expansion of the genetic code. Analysis of amino acid properties and functions explains why amino acids are found in their respective positions in the genetic code.