Molecular Biology: Nature of the Genetic Code Finally Revealed!

RESEARCH HIGHLIGHTS MOLECULAR BIOLOGY However, the size of the codons remained unknown. The authors found that a combination of Nature of the genetic three + or three – mutations, but not two + or two – mutations, could restore the wild-type phenotype. code finally revealed! On the basis of these findings, the authors concluded that a codon was This December marks the fiftieth which carries a mutation in the B cis- most likely to be three nucleotides anniversary of the publication of the tron, produced suppressors, bacterio- long. With a triplex codon made up landmark article by Francis Crick phages that could once again infect a of four potential bases, 64 possible et al., describing the nature of the K strain. Combining the suppressor codons can be formed, which is more genetic code. At that time, many mutations showed that a base was than enough to cover the 20 standard fundamental questions in molecular either added (+ mutation) or removed amino acids; thus, the authors also biology were yet to be answered. The (– mutation) and that a + mutation identified the redundancy in the central dogma, that protein sequence could rescue a – mutation, and vice genetic code. is determined by DNA sequence, had versa. Hence, the authors had identi- But the nature of the code itself been articulated by Crick in 1958, but fied frameshift mutations, in which remained a mystery. In their conclu- how the information was encoded the addition or deletion of a base in sions, the authors stated, optimisti- was unknown. In their paper, Crick the coding DNA sequence causes a cally, that “If the coding ratio is indeed et al. demonstrated that the codons frameshift for the translation machin- 3, as our results suggest, and if the which encode the individual amino ery, leading to a non-functional pro- code is conserved throughout Nature, acids are non-overlapping and consist tein. Correction of the reading frame then the genetic code may well be of three bases. by an additional frameshift mutation solved within the year”. At the time, Amazingly, this fundamental allowed a functional protein to be pro- only a single codon could be assigned finding required just two strains of duced. The authors noticed that this (namely, the phenylalanine codon, Escherichia coli — a K strain and a B worked well with mutations that were UUU), as earlier in the year Marshall strain — and mutants of bacteriophage closely linked, but not with mutations Nirenberg had shown that a continuous T4. Wild-type T4 grows on both that were further apart. They specu- string of uracils was translated into E. coli strains, but a mutant lacking lated that frameshifting introduces a string of phenylalanines. But by cistron B grows only on the B strain. ‘unacceptable’ or ‘nonsense’ codons, 1966 a complete codon table was To mutagenize T4, the authors used which we now refer to as stop codons. produced, based primarily on the acridines, which were thought to be This confirmed the previously held continued work of Nirenberg, who likely to remove or add a single base. notion that the reading frame was worked with cell-free extracts and Mutagenesis of the T4 mutant FC0, non-overlapping. chemically synthesized RNA, work for which he received the Nobel Prize in 1968. Perhaps not much thought is given to these experiments today when translating a DNA sequence to protein, but this stands as a shining example of how basic, and elegant, microbiological techniques have provided insights into fundamental biological questions. Christiaan van Ooij ORIGINAL RESEARCH PAPER Crick, F. H. C. et al. General nature of the genetic code for proteins. Nature 192, 1227–1232 (1961) Figure 1 from Crick et al., reproduced, with permission, from Crick, F. H. C. et al. © (1961) Macmillan Publishers Ltd. All rights reserved. NATURE REVIEWS | MICROBIOLOGY VOLUME 9 | DECEMBER 2011 © 2011 Macmillan Publishers Limited. All rights reserved.

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