Page 249 - 20dynamics of cancer

234 CHAPTER 11

11.2 Progression and Incidence Affect Genetic Variation

The previous section described how genetic variants affect progres-
sion and incidence: the pathway from genes through development to
phenotype. In this section, I analyze how progression and incidence
affect the frequency of variants in populations: the pathway from phe-
notype through natural selection to gene frequency.

EVOLUTIONARY FORCES

Many forces potentially influence gene frequency. The wide range of
alternatives makes it easy to fit some model to the observed distribution
of frequencies, but hard to determine if the fit has any meaning.
Only natural selection provides a simple comparative prediction: the
stronger the deleterious effect of a cancer-predisposing variant on sur-
vival and reproduction, the lower the expected frequency of that variant.
A comparative prediction forecasts the overall tendency or trend, not the
relative frequency of any particular variant.
In this section, I summarize the major evolutionary forces. The fol-
lowing section evaluates the comparative prediction that the deleterious
effects of a variant influence its frequency.

DRIFT
Drift encompasses various chance events. Each copy of a genetic vari-
ant lives an individual and descends, on average, to λ babies. Most pop-
ulations neither grow nor shrink continually, and so the total number
of gene copies remains about the same with λ ≈ 1. If the population
shrunk in one generation to 10% of its current size, then λ = 0.1.
A few simple calculations illustrate the key role of drift for rare vari-
ants. Consider a population of size N with a particular variant at fre-
quency p. In one generation, how much does p typically change if ran-
dom drift is the only evolutionary force acting?
The number of copies of a particular variant is α = p2N, where N is
the size of the population, and 2N is the total number of gene copies—
the factor of 2 arises because each diploid individual carries two copies
of each gene.
In the next generation, the number of variant gene copies follows a
Poisson distribution with an average of αλ in a progeny gene pool of