Potential Impact of Genetic-Code Mutations on Medicine and Health

Abstract

The genetic code encoding amino acid sequences in ribosomal translation consists of an alphabet of 61 triplet codons for 20 amino acids and three chain termination signals. Basically the same universal code is employed by all organisms from the Last Universal Common Ancestor (LUCA)-proximal Methanobacter kandleri (Mka) to humans. This universal code, which has remained invariant for all living species, enables the transplantation of protein-coding genes between different species without loss of function, and constrains the chemical diversity of the encoded amino acids. Over the initial decades following the discovery of the code, its invariance coupled with the lack of any information regarding its origin have led to the view that the code might represent an inexplicable ‘frozen accident’ in the history of life. However, with the formulation of the coevolution theory of the genetic code and its multifaceted supporting evidence, this view has become untenable. Instead, the encoded amino acids are known to comprise two different classes: ten Class 1 amino acids available on prebiotic Earth were incorporated into the protocells as they evolved into life forms, while the ten Class 2 amino acids were produced by early life through biosynthesis. Thus, the later entry of the Class 2 amino acids identified them as end products of cellular evolution, which suggests the plausibility of continuing alterations of the encoded amino acids after an eons-long pause. Accordingly, attempts were made by our group to replace Trp by 4-fluroTrp (4FTrp) from the proteome of Bacillus subtilis. The targeted replacement obtained proved the inherent mutability of the code, and this has stimulated the development of a wide range of mutated codes through a variety of approaches. Hundreds of genetic code mutants have now been successfully isolated from microbes to animals, transforming the code from an immutable construct to a highly malleable molecular device. The effects of such new codes on medicine and health range from treatments for a variety of diseases to the alleviation of food crisis arising from the degradation of the environment and devastation due to natural disasters.