Mutations Are Concentrated at Hotspots

KEY CONCEPT
- The frequency of mutation at any particular base pair is statistically equivalent, 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 DNA in which they occur. When we consider mutations in terms of the alteration of function 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 alter its function. As a result, susceptibility to mutation is roughly proportional to the size of the gene. Are all base pairs in a gene equally susceptible, though, 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? Each is the result of an individual mutational event. Most mutations will occur at different sites, but some will occur at the same position. Two independently isolated mutations at the same site can constitute exactly the same change in DNA (in which case the same mutation has happened more than once), or they can constitute different changes (three different point mutations are possible at each base pair).
The histogram in FIGURE 1. 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). Some sites will gain one, two, or three
mutations, whereas others will not gain any. Some sites gain far more than the number of mutations expected from a random distribution; they might have 10× or even 100× more mutations than predicted by random hits. These sites are called hotspots. Spontaneous mutations can occur at hotspots, and different mutagens can have different hotspots.

FIGURE 1. Spontaneous mutations occur throughout the lacI gene of E. coli, but are concentrated at a hotspot.