King’s amino-acid findability argument

Whereas Kimura (1968) proposed his version of the Neutral Theory of Molecular Evolution as the answer to an esoteric problem of population genetics theory, King and Jukes (1969) proposed a theory driven by the results of macromolecular sequence comparisons. Molecular evolution, in their view, demanded “new rules.” As evidence for neutrality, they pointed to a general correspondence between the frequencies of amino acids in protein sequences, and the frequencies expected from translating randomly generated sequences with the genetic code.

At the bottom left are Met and Trp with 1 codon each and then, proceeding with some variation up and to the right, we have the 2-codon blocks (Cys, His, Tyr, Phe, Gln, Asn, Asp, Lys), Ile with 3 codons, then the 4-codon blocks (Pro, thr, Val, Ala, Gly) then the 6-codon blocks (Leu, Ser, Arg), with Arg being a somewhat extreme outlier due to the CpG effect.

However, King rather quickly recanted on this argument. It is rare for a scientist to do that, so pay attention. King (1971) said that this was not evidence of neutrality, but rather evidence for some kind of indeterministic process dependent on mutation. He explains

“If a gene is in the process of progressive, adaptive evolution, there might very likely be more than one among the thousand or so possible single-step changes that would be evolutionarily advantageous.  Then the first of these to occur by mutation would have the first chance to take over.  The conditions of selection would then be changed, and it would be too late for the other previously potential candidates.  Thus the probability of fixation [probability of origin-and-fixation] of an amino acid is a function of its frequency of arising by mutation, and this will happen more often to amino acids with more codons.  The eventual distribution of amino acid frequencies will reflect, more or less passively, the peculiarities of an arbitrary genetic code, even if most evolutionary changes are due exclusively to Darwinian adaptive evolution.” (p. 7)

King JL. 1971. The Influence of the Genetic Code on Protein Evolution. In:  Schoffeniels E, editor. Biochemical Evolution and the Origin of Life. Viers: North-Holland Publishing Company. p. 3-13

King did not generalize further on this argument. However, we can see this as an instance of a general form of argument in which phenotypes that are over-represented in genotype-space are more findable due to mutation. Amino acids with larger numbers of codons (in the genetic code) occupy a greater volume of sequence space, analogous to phenotypes with large numbers of genotypes in genotype-space, and this makes them more findable by an evolutionary process that explores sequence space (or genotype space) via mutations. So the amino acids with the most codons will tend to be the most common in proteins, and this argument does not require neutrality, but merely a process subject to biases in introduction of amino acid phenotypes.

The form of this argument is analogous to that made by Ard Louis and colleagues in regard to RNA folds that are common in sequence space (Dingle, et al. 2022).

King’s two conference papers in this period reveal important thinking about evolution in discrete spaces. King (1972) gives this image combining states, paths, upwardness, and a fitness landscape. Note that this is not merely a passive depiction of “Maynard Smith’s” concept, but represents creative and synthetic thinking.

And he emphasizes that actually, at any point there are many upward steps and many lateral (neutral) steps, using this diagram:


King JL. 1972. The Role of Mutation in Evolution. In: Sixth Berkeley Symposium on Mathematical Statistics and Probability (eds Le Cam, Neyman, and Scott) Berkeley, California.

King JL. 1971. The Influence of the Genetic Code on Protein Evolution. In:  Schoffeniels E, editor. Biochemical Evolution and the Origin of Life. Viers: North-Holland Publishing Company. p. 3-13.

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