Evidence from glycine transfer RNA of a frozen accident at the dawn of the genetic code

BACKGROUND: Transfer RNA (tRNA) is the means by which the cell translates DNA sequence into protein according to the rules of the genetic code. A credible proposition is that tRNA was formed from the duplication of an RNA hairpin half the length of the contemporary tRNA molecule, with the point at which the hairpins were joined marked by the canonical intron insertion position found today within tRNA genes. If these hairpins possessed a 3'-CCA terminus with different combinations of stem nucleotides (the ancestral operational RNA code), specific aminoacylation and perhaps participation in some form of noncoded protein synthesis might have occurred. However, the identity of the first tRNA and the initial steps in the origin of the genetic code remain elusive. RESULTS: Here we show evidence that glycine tRNA was the first tRNA, as revealed by a vestigial imprint in the anticodon loop sequences of contemporary descendents. This provides a plausible mechanism for the missing first step in the origin of the genetic code. In 448 of 466 glycine tRNA gene sequences from bacteria, archaea and eukaryote cytoplasm analyzed, CCA occurs immediately upstream of the canonical intron insertion position, suggesting the first anticodon (NCC for glycine) has been captured from the 3'-terminal CCA of one of the interacting hairpins as a result of an ancestral ligation. CONCLUSION: That this imprint (including the second and third nucleotides of the glycine tRNA anticodon) has been retained through billions of years of evolution suggests Crick's 'frozen accident' hypothesis has validity for at least this very first step at the dawn of the genetic code. REVIEWERS: This article was reviewed by Dr Eugene V. Koonin, Dr Rob Knight and Dr David H Ardell.