Transcript Document

Incorporating Genetic Drift
In populations of finite size, sampling of gametes
from the gene pool can cause evolution.
Probability of Maintaining the
Same Initial Allele Frequency
The Ultimate Fate of Random Genetic Drift
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
107 pops
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.
Evolution by Genetic Drift : Main Points
1. Allele frequencies fluctuate at random within a population;
eventually, one or another allele becomes fixed.
2. Genetic variation at a locus declines and is eventually lost;
the rate of decline in heterozygosity is used to estimate the
strength of drift: frequency of heterozygotes (H) = 2p(1-p).
3. At any time, the probability of allele fixation ~equals its
frequency at that time.
4. Evolution by genetic drift proceeds faster in smaller
populations; the average time to fixation is 4Ne.
5. Populations with the same initial allele frequency diverge; the
same or different allele maybe fixed but the average allele
frequency remains the same. The frequency of heterozygotes
declines.
Functional constraint: Range of alternative nucleotides
that is acceptable at a site without negatively affecting
the function or structure of a protein.
Fraction of
Selectively Neutral
Mutations
Total Mutation
Rate per Unit Time
Rate of Neutral
Mutation
V0 = vT
fo
Neutral Theory Predicts k = V0 :
Rate of Substitution
(allele)
So,
k = vT fo
k = vT fo
So, rate of substitution will be greatest when fo is 1.0
i.e.
Highest Rate of Substitution is Expected in
Sequence That Does Not Have A Function
Pseudogenes!
Expect an inverse relationship between the intensity of the
functional constraint and the rate of neutral evolution
Got to be careful here!
Given this relationship:
Also, expect higher rates of substitution for
synonymous vs nonsynonymous sites.
Logic:
(1) Mutations that result in amino acid replacements have
a higher probability of causing a deleterious effect on the
structure/function of the protein.
(2) Accordingly, the majority of nonsynonomous mutations
will be eliminated from the population by purifying selection.
(3) As a result, there will be a reduction in the rate of
nonsynonymous substitution vs synonymous substitution.
Why is the rate of substitution at 4-fold sites lower
than the rate within pseudogenes?
Synonymous substitutions are not selectively neutral!
Codon Usage is non-random: species-specific, and
patterns may vary among genes within a genome.
Testing the Neutral Mutation Hypothesis
dN
dS
<
1
When replacements are deleterious
dN
dS
=
1
When replacements are neutral
dN
dS
>
1
When replacements are advantageous
Testing the Neutral Mutation Hypothesis
The neutral theory predicts that
polymorphism within species is correlated positively
with fixed differences between species
i.e.
Genes that exhibit many interspecific differences will
also have high levels of intraspecific polymorphism.
McDonald-Krietman Test
Neutral Prediction:
nonsynonymous fixed
synonymous fixed
=
nonsynonymous polymorphism
synonymous polymorphism
Fixed Differences
Nonsynonymous
Synonymous
% nonsynonymous
21
26
45%
Polymorphisms
2
36
5.3%
G6PDH from D. melanogaster and D. simulans. Eanes et al. 1993
If most nonsynonymous substitutions are adaptive, then
they will increase in frequency and be fixed more rapidly
than neutral alleles.
1.0
advantageous allele
Frequency
neutral allele
0
Time
As a result, they spend less time in a polymorphic state,
therefore contribute less to within species polymorphism.
Another example (N = 6-12 alleles per species for
the coding region).
Fixed Differences
Nonsynonymous
Synonymous
% nonsynonymous
7
17
29%
Polymorphisms
2
42
4.5%
Adh from D. melanogaster, D. simulans, and D. Yakuba
MacDonald and Kreitman 1991
Is the CFTR allele maintained by
mutation/selection balance?
In some populations: Freq of Cystic Fibrosis
Alleles:
2%
Under mutation/selection balance, need:
m = 4 x 10-4
However the actual 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 for island populations.
a) Strong selection for q,
little migration.
Equilibrium points