Page 253 - 20dynamics of cancer

238 CHAPTER 11

These rough guidelines and comparative predictions set a baseline
for expectations of variant allele frequency. When observations deviate
significantly from expectations, then we may turn to forces other than a
balance between deleterious mutation and purging by natural selection.

HIGH PENETRANCE AND EARLY ONSET
Suppose a mutation is expressed in all carriers, and those carriers
die before they have reproduced. In this situation, each case must arise
from a new mutation, and the frequency of mutated alleles, q, is roughly
equivalent to the mutation rate per generation, u, that is, q = u.
Inherited cases of retinoblastoma, Wilms’ tumor, and skin cancer in
xeroderma pigmentosum transmit as dominant mutations. Most indi-
viduals who carry a highly penetrant mutation develop the disease dur-
ing childhood or early life. Without treatment, carriers do not usually
reproduce. These diseases all occur at frequencies, q, of approximately
10 −5 –10 −4 (Vogelstein and Kinzler 2002).
The commonly quoted values for mutation rate, u, tend to be in the
range of 10 −6 –10 −5 per gene per generation (Drake et al. 1998), an order
of magnitude lower than the frequency of cases. For this type of ap-
proximate calculation, a match within an order of magnitude suggests
that we have roughly the right idea about the factors that influence allele
frequencies.
Certainly, other estimates of frequency for these diseases or other
early-onset cancers will not match so closely to the usual estimate of
the mutation rate. A mismatch implicates some force beyond the stan-
dard baseline mutation rate and immediate removal of all mutations by
natural selection. For example, the penetrance may be less than perfect,
some carriers may reproduce, or the gene may be unusually mutable.

AGE OF ONSET AND THE FORCE OF SELECTION
Some inherited mutations have low penetrance or cause later-onset
disease. Natural selection removes a mutation from the population in
proportion both to the probability that it causes disease and to the re-
duction in reproductive success of those individuals who express the
disease (Rose 1991; Nunney 1999, 2003; Frank 2004e). Reduction in
reproductive success depends on the age of onset: later onset has less
effect on transmission of alleles to the next generation. Figure 11.8