The evolution of the genetic code: Impasses and challenges

Abstract

The origin of the genetic code and translation is a "notoriously difficult problem". In this survey we present a list of questions that a full theory of the genetic code needs to answer. We assess the leading hypotheses according to these criteria. The stereochemical, the coding coenzyme handle, the coevolution, the four-column theory, the error minimization and the frozen accident hypotheses are discussed. The integration of these hypotheses can account for the origin of the genetic code. But experiments are badly needed. Thus we suggest a host of experiments that could (in)validate some of the models. We focus especially on the coding coenzyme handle hypothesis (CCH). The CCH suggests that amino acids attached to RNA handles enhanced catalytic activities of ribozymes. Alternatively, amino acids without handles or with a handle consisting of a single adenine, like in contemporary coenzymes could have been employed. All three scenarios can be tested in in vitro compartmentalized systems.

The Future of Origin of Life Research: Bridging Decades-Old Divisions

“…This question seemed for some time to be a mere statistical or even cryptographic problem [112], and a variety of explanations emerged to solve it, most popularly: stereochemical basis for the assignment between nucleic acids and amino acids [113], the development of the code guided by the biosynthetic pathways of amino acids [114], and optimization in order to reduce the severity of mutations [115]. These are not mutually exclusive hypotheses, and the origin of the code might have simultaneously involved several of them [116]. Most likely, the development of the genetic code took place in a continuous expansion [117], a hypothesis supported by functional proteins with reduced amino acid repertoires [118].…”

Physicochemical Foundations of Life that Direct Evolution: Chance and Natural Selection are not Evolutionary Driving Forces

“…While there is an ongoing debate about whether the origin of life started with only RNAs ("RNA world") or with RNAs and peptides ("RNP world"), there is a consensus that the activity of ribozymes (e.g., RNAs that catalyze nucleic acid polymerization) has been enhanced at some points of evolution by their interactions with amino acids or with randomly generated small peptides that could have also stabilized RNAs, which would otherwise be rapidly degraded by hydrolysis ( Figure 3A) [55][56][57]. For example, randomly generated peptides composed of abiogenetically produced amino acids, such as Gly and Asp, can increase the efficiency of replicating ribozymes, as these amino acids play a very important role in the AsnAlaAspPheAspGlyAsp (NADPDGD) peptides found in all polymerases.…”

“…In particular, binding of these amino acids to the catalytic metal ion Mg 2+ could have enhanced polymerization and protected RNA from Mg 2+ -dependent hydrolysis [58]. Coincidentally, a primeval genetic code corresponding to GC-rich and RNY codons (e.g., GGC, GCC, GAC, and GTC) has been proposed, because these codons are the most frequent in coding sequences and correspond to the most metabolically simple amino acids (Gly, Asp, Ala, and Val) that are sufficient to produce stable, folded, and functional proteins [56,59]. A positive feedback loop between nucleic and amino acid polymers could have been initiated by primeval GC-rich RNAs, by first interacting with randomly generated peptides (e.g., made of Gly and Asp), which would then favor the production of more complex peptides through a primeval GC-rich genetic code.…”

“…Polymer production depends on biosynthetic pathways that in turn depend on polymerization products ( Figure 3F). Supporting this interplay between gene expression and biosynthetic pathways, the genetic code likely coevolved with amino acid biosynthetic pathways, as codons starting with A, C, U, or G correspond to amino acids synthetized from oxaloacetate, alpha-ketoglutarate, pyruvate, or from the reductive amination alpha-keto acid, respectively [56,[93][94][95]. A possibility is that the simple amino acids or metabolites that covalently attached to polynucleotides (e.g., proto-tRNAs made of three nucleotides) could have been chemically transformed to give rise to more complex amino acids [95].…”

“…While the genetic code is often described as a "frozen accident" and a cipher, early studies in the 1980s point out some physicochemical properties shared by amino acids and their cognate codons or anticodons. For example, the hydropathy of amino acids correlates with the hydropathy of the principal dinucleotides (excluding the wobble position) of their corresponding anticodons [44,56,57]. Along the same line, some protein physicochemical properties can be shared by their cognate mRNA.…”