Most mutations are spontaneous and occur naturally. However, mutations can also be induced by radiation or chemicals. Mutagens are agents that increase the probability of mutation. The presence of a mutagen can increase the probability of mutation by a factor of 100 or more.

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Some of the most important types of DNA damage induced by mutagens are illustrated in Fig. 14.16, which shows a highly damaged DNA molecule. Some types of damage affect the structure of the DNA double helix. These include breaks in the sugar–phosphate backbone, one of the main mutagenic effects of X-rays. Breaks can occur in just one strand of the DNA or both. Ultraviolet light can cause cross-links between adjacent pyrimidine bases, especially thymine, resulting in the formation of thymine dimers. Covalent bonding between adjacent thymines in a DNA strand causes the double helix to become pinched, both the major groove and the minor groove become wider, and the T–A base pairing is weakened.

Yet another type of structural damage is loss of a base from one of the deoxyribose sugars, resulting in a gap in one strand where no base is present. Spontaneous loss of a purine base is one of the most common types of DNA damage, occurring at the rate of about 13,000 purines lost per human cell per day. Most of these mutations result from the interaction between DNA and normal metabolic by-products. The rate increases with age, and it can also be increased by exposure to oxidizing agents such as household bleach or hydrogen peroxide.

Other types of damage affect the bases themselves. Bases that are chemically damaged tend to mispair. Some bases are damaged spontaneously when reaction with a water molecule replaces an amino group (–NH₂) with an atom of oxygen (=O), which interferes with the base’s ability to form hydrogen bonds with a complement. Some naturally occurring molecules mimic bases and can be incorporated into DNA and cause nucleotide substitutions. Caffeine mimics a purine base, for example (although to be mutagenic, the amount of caffeine required is far more than any normal person could possibly consume).

Chemicals that are highly reactive tend to be mutagenic, often because they add bulky side groups to the bases that hinder proper base pairing. The main environmental source of such chemicals is tobacco smoke. Other chemicals can perturb the DNA replication complex and cause the insertion or deletion of one or occasionally several nucleotides.

Quick Check 3 Earlier, we described the Lederbergs’ experiment, which demonstrated that mutations are not directed by the environment. But mutagens, which are environmental, can lead to mutations. What’s the difference?