A team of scientists has successfully created a strain of E. coli with just 57 codons, proving that life can function with a significantly compressed genetic code. This achievement builds upon previous work by Jason Chin’s group, which previously synthesized an entire E. coli genome with 61 codons, known as Syn61.
To achieve this feat, the researchers removed four codons encoding the amino acid serine, two codons for alanine, and one stop codon from the genetic code. They replaced these codons with synonymous substitutes that produce the same end products. This required recoding over 101,000 codons across a 4 Mb synthetic genome.
The team divided the genome into 38 fragments, each around 100 kb, which were individually synthesized using homologous recombination in yeast. These fragments were then inserted into E. coli using a variant of the Replicon Excision Enhanced Recombination (REXER) method, which combines CRISPR-Cas9 and lambda-red recombination.
The researchers addressed problematic genome regions that resisted recoding or where growth rates were stunted by adjusting gene expression, refactoring overlapping genes, and tweaking codon swaps. They then stitched the fragments together into a series of semi-synthetic strains before mapping and fixing synthetic sequences at each step.
The resulting strain, Syn57, is the most significantly recoded organism to date, demonstrating that life can function with a considerable compressed genetic code. This achievement has significant implications for the development of innovative synthetic polymers and macrocycles, as well as rendering organisms resistant to viral infection, which could make drug manufacturing cheaper and more reliable.
This research was funded by various organizations, including UKRI MRC, the European Research Council, and the Wellcome Trust.
Source: https://www2.mrc-lmb.cam.ac.uk/syn57-represents-a-new-chapter-in-the-genetic-code-of-life