Mutations may affect single base pairs or longer sequences

KEY TERMS:

• A point mutation is a change in the sequence of DNA involving a single base pair.
• A transition is a mutation in which one pyrimidine is replaced by the other and/or in which one purine is replaced by the other.
• A transversion is a mutation in which a purine is replaced by a pyrimidine or vice versa.
• Base mispairing is a coupling between two bases that does not conform to the Watson-Crick rule, e.g., adenine with cytosine, thymine with guanine.
• An insertion is the addition of a stretch of base pairs in DNA. Duplications are a special class of insertions.
• A transposon (transposable element) is a DNA sequence able to insert itself (or a copy of itself) at a new location in the genome, without having any sequence relationship with the target locus.
• A deletion is the removal of a sequence of DNA, the regions on either side being joined together except in the case of a terminal deletion at the end of a chromosome.

KEY CONCEPTS:

• A point mutation changes a single base pair.
• Point mutations can be caused by the chemical conversion of one base into another or by mistakes that occur during replication.
• A transition replaces a G·C base pair with an A·T base pair or vice-versa.
• A transversion replaces a purine with a pyrimidine, such as changing A·T to T·A.
• Insertions are the most common type of mutation, and result from the movement of transposable elements. 

Any base pair of DNA can be mutated. A point mutation changes only a single base pair, and can be caused by either of two types of event (for review see Maki, 2002):

• Chemical modification of DNA directly changes one base into a different base.
• A malfunction during the replication of DNA causes the wrong base to be inserted into a polynucleotide chain during DNA synthesis.

Point mutations can be divided into two types, depending on the nature of the change when one base is substituted for another:

• The most common class is the transition, comprising the substitution of one pyrimidine by the other, or of one purine by the other. This replaces a G·C pair with an A·T pair or vice versa.
• The less common class is the transversion, in which a purine is replaced by a pyrimidine or vice versa, so that an A·T pair becomes a T·A or C·G pair.

The effects of nitrous acid provide a classic example of a transition caused by the chemical conversion of one base into another. Figure 1.20 shows that nitrous acid performs an oxidative deamination that converts cytosine into uracil. In the replication cycle following the transition, the U pairs with an A, instead of with the G with which the original C would have paired. So the C·G pair is replaced by a T·A pair when the A pairs with the T in the next replication cycle. (Nitrous acid also deaminates adenine, causing the reverse transition from A·T to G·C.) 

Transitions are also caused by base mispairing, when unusual partners pair in defiance of the usual restriction to Watson-Crick pairs. Base mispairing usually occurs as an aberration resulting from the incorporation into DNA of an abnormal base that has ambiguous pairing properties. Figure 1.21 shows the example of bromouracil (BrdU), an analog of thymine that contains a bromine atom in place of the methyl group of thymine. BrdU is incorporated into DNA in place of thymine. But it has ambiguous pairing properties, because the presence of the bromine atom allows a shift to occur in which the base changes structure from a keto (=O) form to an enol (–OH) form. The enol form can base pair with guanine, which leads to substitution of the original A·T pair by a G·C pair.

The mistaken pairing can occur either during the original incorporation of the base or in a subsequent replication cycle. The transition is induced with a certain probability in each replication cycle, so the incorporation of BrdU has continuing effects on the sequence of DNA.

Point mutations were thought for a long time to be the principal means of change in individual genes. However, we now know that insertions of stretches of additional material are quite frequent. The source of the inserted material lies with transposable elements, sequences of DNA with the ability to move from one site to another. An insertion usually abolishes the activity of a gene. Where such insertions have occurred, deletions of part or all of the inserted material, and sometimes of the adjacent regions, may subsequently occur.

A significant difference between point mutations and the insertions/deletions is that the frequency of point mutation can be increased by mutagens, whereas the occurrence of changes caused by transposable elements is not affected. However, insertions and deletions can also occur by other mechanisms—for example, involving mistakes made during replication or recombination—although probably these are less common. And a class of mutagens called the acridines introduce (very small) insertions and deletions.