Mutations are concentrated at hotspots

KEY TERMS:

• A hotspot is a site in the genome at which the frequency of mutation (or recombination) is very much increased, usually by at least an order of magnitude relative to neighboring sites.

KEY CONCEPTS:

• The frequency of mutation at any particular base pair is determined by statistical fluctuation, except for hotspots, where the frequency is increased by at least an order of magnitude. 

So far we have dealt with mutations in terms of individual changes in the sequence of DNA that influence the activity of the genetic unit in which they occur. When we consider mutations in terms of the inactivation of the gene, most genes within a species show more or less similar rates of mutation relative to their size. This suggests that the gene can be regarded as a target for mutation, and that damage to any part of it can abolish its function. As a result, susceptibility to mutation is roughly proportional to the size of the gene. But consider the sites of mutation within the sequence of DNA; are all base pairs in a gene equally susceptible or are some more likely to be mutated than others?

What happens when we isolate a large number of independent mutations in the same gene? Many mutants are obtained. Each is the result of an individual mutational event. Then the site of each mutation is determined. Most mutations will lie at different sites, but some will lie at the same position. Two independently isolated mutations at the same site may constitute exactly the same change in DNA (in which case the same mutational event has happened on more than one occasion), or they may constitute different changes (three different point mutations are possible at each base pair).

The histogram of Figure 1.23 shows the frequency with which mutations are found at each base pair in the lacI gene of E. coli. The statistical probability that more than one mutation occurs at a particular site is given by random-hit kinetics (as seen in the Poisson distribution). So some sites will gain one, two, or three mutations, while others will not gain any. But some sites gain far more than the number of mutations expected from a random distribution; they may have 10× or even 100× more mutations than predicted by random hits. These sites are called hotspots. Spontaneous mutations may occur at hotspots; and different mutagens may have different hotspots.