Page 252 - 20dynamics of cancer

INHERITANCE 237

a variant in relation to the genetic background in which the variant lives.
One can think of copies of the variant as living in genetically variable en-
vironments, favored in some environments and disfavored in others.

VARIABLE ENVIRONMENT
External environments also vary. For example, a variant may be disfa-
vored in certain carcinogenic environments and favored in the absence
of those environments. The variable selection can maintain variants that
predispose to cancer at frequencies higher than expected through the
deleterious effects of increased cancer incidence.

MUTATION AND SELECTION
When thinking about cancer, we can often take a simple point of view:
mutation creates deleterious variants that predispose to cancer, and se-
lection removes those deleterious variants from the population. The
other evolutionary forces listed above may or may not act in any particu-
lar case, but deleterious mutation and the purging of those mutations by
natural selection occur continually. The balance between mutation and
selection sets the default against which we should compare observed
frequencies.

MUTATION-SELECTION BALANCE: A COMPARATIVE PREDICTION
It is often difficult to measure precisely the rate of mutation and the
rate at which natural selection purges deleterious mutations. In addi-
tion, other forces such as drift and pleiotropy often affect the frequency
of deleterious, predisposing variants. So any attempt to predict pre-
cisely the frequency of a deleterious variant or to fit some model with
estimated parameters of mutation and selection would mislead: one can
calculate precise predictions or estimate parameters, but those calcula-
tions or estimations would only provide a false sense of precision.
We can estimate the relative strengths of mutation and selection with-
in an order of magnitude or so. Those rough estimates provide guide-
lines to the expected frequencies of deleterious variants. We can also
make two simple comparative predictions. First, as selection against
variants increases, the observed frequency of the variants declines. Sec-
ond, as mutation rate at a particular locus increases, the observed fre-
quency of deleterious variants at that locus increases.