Mistakes in translation don't translate into termination

The evolution of the genetic code remains one of the greatest mysteries in biology. Since the elucidation of the code in the 1960s many hypotheses have been generated to try to explain the assignment of the 64 codons to the canonical 20 amino acids and punctuation. Perhaps the most famous of these, posited by Francis Crick (1), is the “frozen accident” hypothesis, in which the associations of amino acids with their three base codons evolved haphazardly, were fixed in place as organisms became more complex, and thereafter could change only with great difficulty. In this scenario, many mutations would result in amino acid substitutions that would greatly impair the functionality of proteins. Alternatively, the genetic code may have undergone a period of optimization before fixation, and amino acid substitutions would be more chemically and functionally conservative.

Choosing between these (and other) scenarios is extremely difficult, though, because all of biology has evolved for many billions of years in the context of the almost universal code and thus has already been highly optimized for the extant code irrespective of whether there was preoptimization or not. At best, we can examine the nature of the chemical constraints on the current genetic code via perturbation and directed evolution experiments. Although many attempts have been made to alter the genetic code by amino acid replacement (2, 3) and codon reassignment (4, 5), few have looked at the global effects of altering the genetic code on an organism until now. To probe the degree and nature of selective pressures that constrain the genetic code, Bacher et al. (6) in this issue of PNAS explore …