In The Design Matrix, I explore the manner in which cytosine deamination, one of the most common DNA lesions, might facilitate evolution by substituting a pool of random amino acids for a pool of hydrophobic amino acids (I first described this back in 2002 ). But the story doesn’t stop there.

In 2005, David Orren published a paper (The irresistible resistance of nonsense: Evolutionary adaptation of termination codons to minimize the effects of common DNA damage. DNA Repair 4: 1208-1212) showing that all three termination codons are completely resistant to cytosine deamination (in the excerpt below, TM = transcriptional mutagenesis):

However, the sequences of termination codons also protect them from the effects of cytosine deamination of DNA ( Fig. 2). The UAA ochre codon derived from template ATT is obviously not susceptible to changes caused by cytosine deamination. The UAG (amber) and UGA (opal) termination codons are generated from template ATC and ACT, respectively. However, cytosine deamination to uracil in template ATC and ACT yields ATU and AUT, respectively. Thus, termination codon sequences are resistant or well-adapted to TM resulting from not only guanine lesions but also cytosine deamination. Intriguingly, the predominance of the ochre codon as the termination signal for prokaryotic genes [9] might be explained by cytosine deamination events that ultimately result in convergence of ATC and ACT sequences to ATT in the template DNA.

So the same code that appears to funnel cytosine deamination events toward a particular type of amino acid substitution also completely prevents cytosine deamination from eliminating the stop codons.

Orren notes:

Thus, in the face of common DNA damage, the design of the genetic code promotes mutations that favor substitutions over C-terminal extensions in even greater proportions than would be predicted by a completely random induction of codon changes. In evolutionary terms, this tendency towards less disruptive changes in protein structure and function may have more often allowed survival while promoting adaptation to environmental conditions.

And

Thus, the genetic code may be tailored to facilitate evolution via TM and retromutagenesis in prokaryotes and possibly in unicellular eukaryotes.

The puzzle pieces are slowing fitting together.