The genetic code employs three stop codons – UGA, UAA, and UAG. We have already seen that these codons are perfectly immune to the effects of cytosine deamination. In other words, the code buffers against mutations that will mistakenly produce elongated proteins by turning a stop codon into a sense codon (a codon that codes for an amino acid).
But another question arises – why are there three stop codons? Since one stop codon would be sufficient for the purposes of signaling termination during protein synthesis, why the extra two? What’s more, by having three stop codons instead of one, we increase the chance of having a nonsense mutation, where a sense codon is mutated into a stop codon. Nonsense mutations would thus produce truncated proteins. Such nonsense mutations are a problem for the cell, as evidenced by the need for an RNA surveillance system known as nonsense-mediated decay. So again, why not just use one stop codon?
To understand why life uses three codons, I propose that we tap into the engineering concept of design tradeoffs. NASA explains this strategy as follows:
Conceptual design involves a series of tradeoff decisions among significant parameters – such as operating speeds, memory size, power, and I/O bandwidth – to obtain a compromise design which best meets the performance requirements. Both the uncertainty in these requirements and the important tradeoff factors should be ascertained. Those factors which can be used to evaluate the design tradeoffs (usually on a qualitative basis) include:
• Development Status and Cost
We have good reason to think a design tradeoff is in play. Ciliates have reassigned two of their three stop codons such that they code for glutamine. Thus, the blind watchmaker has the ability to strip away two of the three stop codons, yet has not done this with most organisms. This tells us that there is a long-term beneficial aspect of the code’s design. So what might it be?
A first possible explanation is that the use of three codons emphasizes expandability and adaptability, where the code was designed to facilitate future evolution. That is, two of the three stop codons are poised as place-holders, whereby the blind watchmaker could more readily reassign them a new amino acid if needed. And sure enough, a 21st and 22nd amino acid have been incorporated into living organisms since the code came into existence. Selenocysteine, the 21st amino acid which is used by bacteria, archaea, and eukarya, is coded for by UGA. Pyrrolysine, the 22nd amino acid which is used by some methanogenic archaea, is coded for by UAG. We would thus predict that if further new amino acids have been added to specific lineages, they will be coded for by one of the stop codons.
Another explanation concerns maintainability, whereby the risk of nonsense mutations is not only addressed with nonsense mediated decay, but is balanced against the risk of frameshift mutations.
In a frameshift mutation, a single base is added or deleted, thus altering the reading frame of the transcript downstream of the site of mutation. This means that the coding sequence downstream of the mutation codes for a random string of amino acids that could gunk up the cell. Also lost in the frameshift is the termination codon, meaning this string of random gunk could be quite long. Having three stop codons instead of one increases the chance that a new stop codon will be encountered downstream of the site where the original stop codon was positioned. In other words, just as three stop codons increase the chance of a nonsense mutation, they likewise increase the chance a stop codon will be encountered after a frameshift has occurred.
What is most intriguing here is that a recent scientific study by Itzkovitz and Alon has shown that life’s code is among the very best at terminating frameshifts :
Here, we consider whether robustness to translational frame-shift errors may be linked to the structure of the genetic code. We tested all alternative codes for the mean probability of encountering a stop in a frame-shifted protein-coding message. We find that the real genetic code encounters a stop more rapidly on average than 99.3% of the alternative codes (Fig. 3). The real code aborts translation eight codons earlier than the average alternative code (15 codons vs. 23 codons).
Feast your eyes on figure 3:
So we can begin to see the engineering concept of design tradeoffs helps to explain why life uses three instead of one stop codon. If life used only one stop codon, it is doubtful a 21st and 22nd amino could have been tapped and the effects of frameshifts would likely be more severe. By using three codons, the risk of nonsense mutations is increased, yet this can be handled by processes such as nonsense-mediated decay.
But let me end with a tease. The explanation most likely goes much deeper than this and perhaps takes us into the realm of cybernetics.
1. Shalev Itzkovitz and Uri Alon. 2007. The genetic code is nearly optimal for allowing additional information within protein-coding sequences. Genome Res. 17: 405-412