A reason for cytosine deamination

A few people have notified me to let me know that front-loading is being discussed on UD by someone with the moniker ‘genomicus.’ In one place, genomicus states that cytosine deamination is a prediction of front-loading.  Someone else with the moniker “eigenstate” disagrees and writes:

The fail point here in this item is “so why would a front-loader choose cytosine as a base in DNA?”. It’s not sufficient to offer us *a* reason why you think cytosine would be chosen (and this is particularly devastating if you are offering this putative prediction in the context of an “intelligent design” explanation, an explanation with an unknown, inscrutable, mysterious designer). The choice must follow NECESSARILY from the hypothesis.

You are quite conspicuously working backwards from your conclusion. Coming up with a plausible choice — and given an unspecified, unknown, potentially omniscient and omnipotent designer, ALL choices are plausible — does not ground a prediction. First you lay out the hypothesis, the proposed mechanism, and then you deduce from that NECESSARY implications that proceed from that. If you can affirm what is entailed from your model, you got something! Sometimes those predictions are trivial or banal, and so don’t carry much weight. Other times they just don’t distinguish the hypothesis from other, competing hypotheses. But in this case, if you COULD establish that such a choice was ENTAILED from your proposed model, that would be quite substantial, indeed, I think.

I would not agree with genomicus that front-loading predicts the cytosine deamination story.  That whole story is more subtle and complex than that.  Let me explain.

The SRP, Alu Elements, and Nudging

I’ve combined the essays about the signal recognition partcle, Alu elements, cytosine deamination, all connected by front-loading. All 11, 465 words of it.

Methylation – Focusing the Effects of Cytosine Deamination

Back around 2002, I noted that the genetic code appears to funnel one of the most common  base pair substitutions, the C-to-T transitions caused by deamination of the cytosine.  Put simply, codons containing a C specified a wide range of amino acids, but when that C is converted to T, the new set of codons all converge on the most hydrophobic amino acids.  The original analysis is found here.

To see this for yourself, the figure below represents a hydrophobicity scale for the 20 amino acids based on 47 published attempts to quantify hydrophobicity:

Source

Now consider the effect of cytosine deamination using this scale:

Scale on left are the amino acids coded for by C-containing codons which is converted to scale on right by the deamination of those cytosines.

But what if we did the same analysis, but this time restrict our focus to the cytosines that are followed by guanines – the CpG sequences discussed here, given that such sequence is the most likely to exploit the effects of deamination?

Nudging the nudge

We have seen that the Alu element is poised to generate binding sites for multiple transcription factors involved in development.  Even more interesting is the manner in which the process of cytosine deamination can easily create several of these transcription factor binding sites.  It’s as if we have two nudges, working together, to facilitate the evolution of primates.

Yet there is more to the story.  Recall that the cytosine deamination events occur at CpG sites.This is simply where a cytosine (C) is followed by a guanine (G).  Why is this?

You too, p53?

p53 has been called the “Guardian of the genome” and is commonly known as a tumor-suppressor gene – a gene that suppresses the formation of cancer.  Normally, the cell expresses low levels of the p53 protein, but if the genome is damaged, p53 levels rise and in turn activate several programs that will arrest the cell cycle and attempt to repair the DNA damage.  If the genome cannot be repaired, p53 will then activate programmed cell death and the cell will die rather than pass on the damage to future generations.

Cytosine Deamination and Evolution

It has been argued that no engineer would have used cytosine as part of the genetic material because of its predisposition for deamination. But it’s exactly this predisposition that might cause an engineer of evolution to include it.

Life itself appears to have been designed to minimize errors. The universal nature of the proof-reading/repair machinery, the optimized genetic code, and the G/C:A/T parity code all converge on this point. Yet despite this design logic, there is the interesting fact that cytosine is especially prone to deamination, where the removal of its exocyclic amino group converts it into uracil (a base normally found in RNA). Uracil does not exist in DNA, thus it can be effectively detected and removed by repair enzymes. However, if not detected and repaired, it can base pair with adenine, meaning that it would specify adenine during DNA replication. In a subsequent round of replication, the adenine in turn would specify thymine. The bottom line is that spontaneous deamination of cytosine can lead to a base substitution known as a transition, where C is replaced by T (and G is replaced by A on the other strand of DNA). We might expect such mutations to be quite common, as the rate constant for cytosine deamination at 37 degree C in single stranded DNA translates into a half-life for any specific cytosine of about 200 years. In fact, such high rates of deamination led researchers Poole et. al to complain of “confounded cytosine!” [1]

We would thus seem to have two contradictory lines of evidence. On one hand, there is the growing list of evidence to support the hypothesis that error correction was an important principle guiding the design of life. Yet the incorporation of cytosine works against such efforts, given its predisposition to spark a mutation. In fact, Poole et al. go so far as to argue, “Any engineer would have replaced cytosine, but evolution is a tinkerer not an engineer.” From a design perspective, how might these contrary dynamics be reconciled? That is, given the emphasis on error correction, why would an engineer include cytosine?