Transcript Is the CFTR allele maintained by mutation/selection balance?

Is the CFTR allele maintained by
mutation/selection balance?
In some populations: Fraction infected with Cystic Fibrosis:
2%
Under mutation/selection balance (eq. Freq. of q = m / s), need:
m = 4 x 10-4
However the actual (estimated) rate is 6.7 x 10-7
too low!
Cultured mouse cells with CFTR genotypes
The fitness cost
of dF508 / dF508
with respect to
Pseudomonas
is balanced by the
fitness advantage
of dF508 / +
with respect to
Salmonella
Incorporating Migration
Island
Geneflow
Continent
Migration can alter
allele and genotype
frequencies.
Migration is a
homogenizing
force; it prevents
divergence of
populations
Lake Erie
Water Snakes
Banded vs Unbanded
Natural Selection for Unbanded Forms on Islands
Banded
Unbanded
Incorporating Migration
Banded alleles
Island
Opposed by
Natural Selection
Continent
It is possible to calculate
the change in frequency
of the banded allele (q)
as a function of q.
Change in frequency of the unbanded
allele (q) as a function of q.
Equilibrium points
Incorporating Genetic Drift
In populations of finite size, sampling of gametes
If 10 zygotes are sampled
from a population with
p = 0.6, q = 0.4.
Probability of Maintaining the
Same Initial Allele Frequency
The Ultimate Fate of Genetic Drift:
Random Fixation or Loss of Alleles
The Effects of Drift are More Pronounced in Smaller Populations
8 pops
The frequency
of heterozygotes
decreases under
drift.
Hg+1 = Hg[1-1/2N]
N=16
N=9
Ne = 4NmNf / (Nm + Nf)
Effective population size
N=16
Rate of Evolution by Genetic Drift
Rate of evolution
equals rate that
an allele is fixed
at a locus.
Depends upon: (2Nu) number of mutations arising at locus
per generation, and initial frequency of new allele (1/2N)
K = 2Nm x 1/2N = m
rate of allele substitution = rate of mutation!
Neutralist view: allele substitution and polymorphism
are determined by the same evolutionary process.
•
Mutation provides a continual supply of new alleles.
Because many alleles are neutral
or effectively neutral, alleles
becomes fixed or lost from a
population as a result of
genetic drift.
•
Polymorphism is simply a snapshot of a continuous
process of mutational input and subsequent random
extinction or fixation of alleles.
Mootoo Kimura’s concept of neutralism is illustrated in the
following diagram from his original paper.
Selectionist view: allele substitution and polymorphism
are determined by different, selective processes.
• Mutation yields advantageous
alleles that are driven to fixation by
positive natural selection.
• Two or more alleles are maintained
at a locus in a population by
over dominance.