Neutral mutations

Kimura [3] and King and Jukes [4] proposed a way to solve both empirical problems. If the vast majority of amino acid substitutions are selectively neutral, then substitutions will occur at approximately a constant rate (assuming that mutation rates don't vary over time) and it will be easy to maintain lots of polymorphism within populations because there will be no cost of selection. I'll develop both of those points in a bit more detail in just a moment, but let me first be precise about what the neutral theory of molecular evolution actually proposes. More specifically, let me first be precise about what it does not propose. I'll do so specifically in the context of protein evolution for now, although we'll broaden the scope later.

• The neutral theory asserts that alternative alleles at variable protein loci are selectively neutral. This does not mean that the locus is unimportant, only that the alternative alleles found at this locus are selectively neutral.
  • Glucose-phosphate isomerase is an esssential enzyme. It catalyzes the first step of glycolysis, the conversion of glucose-6-phosphate into fructose-6-phosphate.

  • Natural populations of many, perhaps most, populations of plants and animals are polymorphic at this locus, i.e., they have two or more alleles with different amino acid sequences.

  • The neutral theory asserts that the alternative alleles are selectively neutral.

• By selectively neutral we do not mean that the alternative alleles have no effect on physiology or fitness. We mean that the selection among different genotypes at this locus is sufficiently weak that the pattern of variation is determined by the interaction of mutation, drift, mating system, and migration. This is equivalent to saying that $N_es < 1$, where $N_e$ is the effective population size and $s$ is the selection coefficient on alleles at this locus.
  • Experiments in Colias butterflies, and other organisms have shown that different electrophoretic variants of GPI have different enzymatic capabilities and different thermal stabilities. In some cases, these differences have been related to differences in individual performance.

  • If populations of Colias are large and the differences in fitness associated with differences in genotype are large, i.e., if $N_es > 1$, then selection plays a predominant role in determining patterns of diversity at this locus, i.e., the neutral theory of molecular evolution would not apply.

  • If populations of Colias are small or the differences in fitness associated with differences in genotype are small, or both, then drift plays a predominant role in determining patterns of diversity at this locus, i.e., the neutral theory of molecular evolution applies.

In short, the neutral theory of molecular really asserts only that observed amino acid substitutions and polymorphisms are effectively neutral, not that the loci involved are unimportant or that allelic differences at those loci have no effect on fitness.