Patterns of nucleotide and amino acid substitution

So I’ve just suggested that the neutral theory of molecular evolution explains quite a bit, but it also ignores quite a bit. The derivations we did assumed that all substitutions are equally likely to occur, because they are selectively neutral. That isn’t plausible. We need look no further than sickle cell anemia to see an example of a protein polymorphism in which a single amino acid difference has a very large effect on fitness. Even reasoning from first principles we can see that it doesn’t make much sense to think that all nucleotide substitutions are created equal. Just as it’s unlikely that you’ll improve the performance of your car if you pick up a sledgehammer, open its hood, close your eyes, and hit something inside, so it’s unlikely that picking a random amino acid in a protein and substituting it with a different one will improve the function of the protein.