Optimisation is not Always Perfection (or Vice Versa)

The Great 2013 Catch-upIn Yeast Survive as They ‘Fail to Optimize’ (10 April 2013) Brian Thomas stumbles upon an important biological truth: what looks better on paper, when considering only a single part of a biological system, can still be bad for the survival of the organism as a whole.

He’s talking about a news article in Nature from February summarising two papers investigating how differing choices in codons that code for the same amino acid can affect the efficiency of the (here, circadian rhythm-related) proteins that they create, one studying a type of fungus and the other a bacterium. (None of those three articles are open access, but a pdf of the bacterium paper is here, while a helpful blog post can be read here.)

The Nature news article explains the codon-bias idea like so:

Codon-usage bias stems from the fact that there is redundancy in the process of protein coding. Twenty standard amino acids are used to form proteins, but because the three-letter codon code gives 64 possible combinations (the four nucleotide bases taken three at a time), there is the potential for more than one codon for each amino acid. Transfer RNA (tRNA) molecules recognize codons and carry the appropriate amino acid to the ribosome (the cellular machine that synthesizes proteins), and tRNAs can be expressed at different levels. It is thought that highly used codons correlate with abundant matching tRNA molecules, and that genes evolve to optimize the efficiency of protein translation on the rationale that faster protein synthesis yields more protein and that this is good. According to this concept, the translation rate depends on the codons used by the encoding gene, and in vitro studies suggest that this can not only affect the amount of protein made, but also influence the process of folding a polypeptide chain into the correct three-dimensional protein structure.

Mr Thomas talks about the idea of different codons coding for the same amino acid as “alternate spellings for the same genetic ‘words,'” and this is an analogy that can be taken further. Imagine you’re touch-typing on a standard qwerty keyboard (I don’t have to, but you might given that you’re reading and not writing this) and you want to type as fast as humanly possible. One way to do this would be to change your preferred spellings of some of the words that you use: replacing ‘c’ with ‘k’ where possible, as ‘k’ is on the home row but ‘c’ is not, and using the British ‘s’ spelling of words that Americans spell with a ‘z’ for the same reason. In theory, at least, there should be some small speed and efficiency advantage from such a change.

The circadian rhythms of the fungus and the bacterium are very different, but both involve proteins that must be manufactured by the cell and the genes for neither of them were optimised in this way. Because this is the 21st century the researchers were able to modify the genes so that they observed the codon-bias rules optimal for their respective cells. They got contradictory results.

In the case of the fungus the optimised gene produced its protein faster, but it would fail to fold properly. This miss-folded protein would then fail to function as well as it ought, potentially bringing the whole clock down with it. Oops. You can see then why this wouldn’t be the natural state of the organism.

In contrast, when the bacterium’s gene was modified the end result was a much more robust clock cycle tied more closely to the 24-hour day/night environment it was in. Counter-intuitively, this turned out to be a bad thing. As the news article explains:

The explanation for this goes back to circadian first principles: clocks are evolutionarily advantageous because they help to coordinate activities in organisms such that they happen at appropriate times of day. In this case, the bacterium’s natural rhythm at low temperature can be as long as 30 hours. Circadian-entrainment theory and practice both show that when a 30-h clock is entrained to a 24-h light–dark cycle, it must do so with a significantly later phase angle — so late that clock-regulated activities are driven to later and inappropriate times. Thus, the temperature conditionality of the wild-type system, in which rhythms are weakened or lost at low temperatures, is good: no clock is better than a maladaptive clock.

To take it back to the typing analogy, sometimes “as fast as humanly possible” isn’t actually the ideal (or perhaps just not worth the effort). But what is Mr Thomas’ problem then? He concludes his own article by saying:

Far from being failures, these circadian clocks are clearly fine-tuned—they regulate biological clocks by precision design specifications. The experiments, showing that just a subtle tinkering disrupts the clocks, demonstrate that only a Divine Horologist could have added the required precision to genes and proteins all at once in the beginning.

These systems may well be “fine tuned” but that in no way means that evolution could not have produced them. To begin with, the situation here is that the normal state (no bias) is the preferable one, while it is the state that would require further modification (some codon bias) that is detrimental – no fine-tuning evolution would actually have needed to take place here. More generally, however, natural selection is perfectly capable of fine-tuning a system like this so that it works better. There is no “Divine Horologist” required here, with the requirement that the fine-tuning be there from the beginning unnecessary.


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