Frozen Accident Pushing 50: Stereochemistry, Expansion, and Chance in the Evolution of the Genetic Code

Abstract

Nearly 50 years ago, Francis Crick propounded the frozen accident scenario for the evolution of the genetic code along with the hypothesis that the early translation system consisted primarily of RNA. Under the frozen accident perspective, the code is universal among modern life forms because any change in codon assignment would be highly deleterious. The frozen accident can be considered the default theory of code evolution because it does not imply any specific interactions between amino acids and the cognate codons or anticodons, or any particular properties of the code. The subsequent 49 years of code studies have elucidated notable features of the standard code, such as high robustness to errors, but failed to develop a compelling explanation for codon assignments. In particular, stereochemical affinity between amino acids and the cognate codons or anticodons does not seem to account for the origin and evolution of the code. Here, I expand Crick’s hypothesis on RNA-only translation system by presenting evidence that this early translation already attained high fidelity that allowed protein evolution. I outline an experimentally testable scenario for the evolution of the code that combines a distinct version of the stereochemical hypothesis, in which amino acids are recognized via unique sites in the tertiary structure of proto-tRNAs, rather than by anticodons, expansion of the code via proto-tRNA duplication, and the frozen accident.

Rooted tRNAomes and evolution of the genetic code

“…We posit that cloverleaf tRNA is the molecular archetype around which translation systems and the genetic code evolved. Evolution of the genetic code was recently comprehensively reviewed, but issues remain unresolved [ 1 , 2 ]. We posit that to grasp code evolution requires a focus on tRNA evolution.…”

“…A hierarchy is observed for the importance of the three tRNA anticodon positions for translation [ 2 , 14 ]. The middle (second) position of the anticodon is most important for translational fidelity, followed by the third position and then followed by the wobble (first) position.…”

Enrichment of Circular Code Motifs in the Genes of the Yeast Saccharomyces cerevisiae

“…Numerous hypotheses have been formulated concerning the evolution of the ancient genetic codes into the modern standard genetic code (reviewed in [ 24 ]). For example, several lines of evidence have been used to classify the standard 20 amino acids into 'early' and 'late' ones.…”

“…For example, several lines of evidence have been used to classify the standard 20 amino acids into 'early' and 'late' ones. Ten early amino acids ( EAA ) have been consistently identified in prebiotic chemistry experiments as well as in meteorites, in the following order of abundance: (reviewed in [ 24 ]). The ten late amino acids are entirely biogenic and were probably recruited into the code after the evolution of the respective biosynthetic pathways, possibly in complementary pairs.…”

Entropy Production as the Origin of Information Encoding in RNA and DNA

“…A number of theories have attempted to addressed this information problem by considering the origin of the association between amino acids and their cognate codons or anticodons. The "stereochemical theory" suggests that amino acids became linked with their codons or anticodons based on stereo-chemical affinity [1][2][3], while the "frozen accident theory" [4,5] suggests that such links arose purely by chance but once established would have remained so since any changes would have been highly deleterious to protein construction and surely detrimental to the organism. The "co-evolutionary theory" [6] suggests instead that the structure of the codon system is primarily an imprint of the prebiotic pathways of amino-acid construction, which remain recognizable in contemporary enzymatic pathways of amino acid biosynthesis.…”