Another important reason that complex proteins can evolve against seemingly long odds is that evolution proceeds stepwise through the processes of mutation and selection. A mutation is a change in the sequence of a gene. The process of mutation is discussed in Chapter 14, but for now all you need to know is that mutations affecting proteins occur at random in regard to their effects on protein function. In protein-coding genes, some mutations may affect the amino acid sequence; others might change the level of protein expression or the time in development or type of cell in which the protein is produced. Here, we will consider only those mutations that change the amino acid sequence.

By way of analogy, we can use a simple word game. The object of the game is to change an ordinary English word into another meaningful English word by changing exactly one letter. Consider the word GONE. To illustrate “mutations” of the word that are random with respect to function (that is, random with respect to whether the change will yield a meaningful new word), we wrote a computer program that would choose one letter in GONE at random and replace it with a different random letter. The first 24 “mutants” of GONE are:

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Most of the mutant words are gibberish, corresponding to the biological reality that most random amino acid replacements impair protein function to some extent. On the other hand, some mutant proteins function just as well as the original, and a precious few change function. In the word-game analogy, the mutants that can persist correspond to meaningful words, those words shown in red.

In a population of organisms, random mutations are retained or eliminated through the process of selection among individuals on the basis of their ability to survive and reproduce. This process was introduced in Chapter 1 and is considered in greater detail in Chapter 21, but the principle is straightforward. Most mutations that impair protein function will be eliminated because, if the function of the nonmutant protein contributes to survival and reproduction, the individuals carrying these mutations will leave fewer offspring than others. Mutations that do not impair function may remain in the population for long periods because their carriers survive and reproduce in normal numbers; a mutation of this type has no tendency to either increase or decrease in frequency over time. In contrast, individuals that carry the occasional mutation that improves protein function will reproduce more successfully than others. Because of the enhanced reproduction, the mutant gene encoding the improved protein will gradually increase in frequency and spread throughout the entire population.

In the word game, any of the mutants in red may persist in the population, but suppose that one of them, GENE for example, is actually superior to GONE (considered more euphonious, perhaps). Then GENE will gradually displace GONE, and eventually GONE will be gone. In a similar way that one meaningful word may replace another, one amino acid sequence may be replaced with a different one in the course of evolution.

A real-world example that mirrors the word game is found in the evolution of resistance of the malaria parasite to the drug pyrimethamine. This drug inhibits an enzyme known as dihydrofolate reductase, which the parasite needs to survive and reproduce inside red blood cells. Resistance to pyrimethamine is known to have evolved through a stepwise sequence of four amino acid replacements. In the first replacement, serine (S) at the 108th amino acid in the polypeptide sequence (position 108) was replaced with asparagine (N); then cysteine (C) at position 59 was replaced with arginine (R); asparagine (N) at position 51 was then replaced with isoleucine (I); finally, isoleucine (I) at position 164 was replaced with leucine (L). If we list the amino acids according to their single-letter abbreviation in the order of their occurrence in the protein, the evolution of resistance followed this pathway:

NCSI → NCNI → NRNI → IRNI → IRNL

where the mutant amino acids are shown in red. Each successive amino acid replacement increased the level of resistance so that a greater concentration of drug was needed to treat the disease. The quadruple mutant IRNL is resistant to such high levels that the drug is no longer useful.

Depicted according to stepwise amino acid replacements, the analogy between the evolution of pyrimethamine resistance and the word game is clear. It should also be clear from our earlier discussion that hundreds of other mutations causing amino acid replacements in the enzyme must have occurred in the parasite during the course of evolution, but only these amino acid changes occurring in this order persisted and increased in frequency because they conferred greater survival and reproduction of the parasite under treatment with the drug.

Quick Check 4 What do you think happened to the mutations that decreased survival or reproduction of the parasites?