Mutation Mechanisms - When organisms copy their DNA, mistakes are occasionally made. These mistakes may be random errors that occur during copying, or they may be the result of damage the DNA has sustained from radiation or chemical mutagens, substances that produce mutations (Table 7.1). These alterations will appear as mutations in the DNA of the next and subsequent generations. There are two basic kinds of changes in the DNA sequence that may give rise to mutations in proteins.

1. Replacement of DNA Bases by Others - Replacement of bases in a section of DNA encoding a gene can have several possible consequences.

a. The base change may not affect the protein sequence at all. The change may occur in an intron or other region of the DNA that does not code for protein. But even if it is in a protein-coding region (exon), the replacement will make no difference in the protein sequence if the new codon codes for the same amino acid as the original one. The redundancy of the genetic code (see here) is such that fairly frequently a base change does not alter the amino acid sequence of the protein product.

b. An amino acid residue in the original protein may be replaced by a different one in the mutated protein; this type of replacement is called a missense mutation (Figure 7.21a).

c. If the codon for an amino acid residue within the original protein is changed to a stop codon, the protein will be terminated prematurely and usually will be nonfunctional (Figure 7.21b). This is called a nonsense mutation.

d. Sometimes the opposite happens-a stop codon mutates into a codon for an amino acid residue. In this case translation continues past the original stopping point, elongating the chain until the next stop codon is encountered.

Base substitutions may, in some cases, be neutral in effect, either not changing the amino acid coded for or changing it to another that functions equally well at that position in the protein. More often, the result is deleterious. Nonsense mutations, for example, almost always result in destruction of protein function. Occasionally mutations due to base substitutions increase the efficiency of a protein. When they do, the organism having the mutation may have a survival advantage over those that don't, allowing it to pass on the mutation to subsequent generations. This is one way that organisms adapt and evolve.

2. Deletions or Insertions of Bases in the Gene - Deletions or insertions in the gene may be large or small. Large insertions or deletions in coding regions almost invariably prevent the production of useful protein. The effect of short deletions or insertions depends on whether they involve multiples of three bases.

a. Deletion or insertion in a coding region of any number of bases other than a multiple of three has a drastic effect: It causes a shift in the reading frame during translation, resulting in a meaningless change in the amino acid sequence in the C-terminal direction from the point of mutation (Figure 7.21c). Such frameshift mutations are sometimes called gibberish mutations because the amino acid sequence is usually rendered meaningless.

b. Insertion or deletion of multiples of three bases do not affect coding of the protein outside the site of the insertion or deletion. Instead, the consequence is the deletion or addition of a corresponding number of amino acid residues. This may or may not affect the function of the protein made from the sequence.

Frameshift mutations almost always result in destruction of protein function.

By accumulating many small mutations over millions of years, proteins gradually evolve. The diversity of functions that they can collectively perform is increased by two other phenomena:

Gene Duplications - On rare occasions, events in a cell lead to a situation where two copies of the same gene are present. If there is no selective pressure, the two copies may evolve independently. One copy may continue to express the protein fulfilling the original function, but the other may evolve through mutations into an entirely different protein with a new function.

Gene Rearrangements - Fusion of two or more initially independent genes leads to the production of multidomain proteins exhibiting new combinations of functions in a single protein. Intervening sequences in eukaryotic genes (introns) are not used for coding, so they are places where genes can be easily cut and recombined in the process of genetic recombination. The mechanisms of recombination are described here. If an exon from one gene, which codes for a protein region with physiological function B, is inserted into an intron region in a gene for a protein carrying function A, the new hybrid protein is capable of both functions A and B and may serve a new physiological function.

Through the combined effects of mutations, gene duplication, and genetic rearrangement, organisms can develop new proteins. The process of organismal evolution is largely a consequence of this molecular evolution of proteins.