Mendelian Population Genetics

Evolution: change in allele frequencies within

a population over time

A mouse is a vehicle for mouse

gene replication

Mice with Aa
genotypes

IF no mutationGametes

IF random mating

Zygotes

Sum = 1

Then zygotes grow up to be adults

IF no survival selection, and IF no

biased migration, and IF no biased
random death

THEN you get these adult genotypes, which

produce gametes

Adults produce gametes IF no

mutation.

Those are the same allele frequencies

we started with!! A = 0.6 a = 0.4

There was no evolutionary

change.IF

No mutation
Random mating
No biased migration
No biased selected mortality (selection)
No biased random mortality (drift)

The general case

Developed by Hardy 1908

Mind your ps and qs

If p = frequency of A1 allele
And q = frequency of A2 allele
And if there are only two alleles in the
population at this locus
Then p + q = 1
Alternatively q = 1- p

Randomly combining gametes in

the general case
Sperm are A1 with
probability p
Eggs are A1 with
probability p
So A1A1 zygotes
are produced with
probability of p X p
= p2

And so on.

A1A1 genotype has frequency of p2

A1A2 genotype has frequency of pq
A2A1 genotype has frequency of pq
A2A2 genotype has frequency of q2

But A1A2 is the same as A2A1 = 2 pq

Frequencies must add to 1
p2 + 2pq + q2 = 1

Hardy-Weinberg Equilibrium
If a simple set of assumptions holds, then
the allele frequencies in a population will
not change
If we symbolize allele frequencies as p and
q, then genotype frequencies are p2, 2pq,
and q2

What are those simple assumptions?

No selection: genotypes survive at equal
rates (i.e. no survival selection) and
contribute gametes to the next generation
equally (i.e. no sexual selection)
No mutation: the alleles we are accounting
for stayed the same, none disappeared or
were created anew by mutation

What are those simple assumptions?

No biased migration: genotypes do not enter or
exit the population non-randomly
No biased random events: genotypes do not get
zapped by lightning (or whatever) non-randomly;
if so, called genetic drift
Mating is random by genotype. Violating this
assumption affects genotype frequency, not allele
frequency. This is NOT the same thing as sexual
selection (unequal gametic contribution of
genotypes).

What a bunch of malarcky!

Obviously those five conditions are almost
never met!
So when those conditions are not met, allele
frequencies WILL change, i.e. evolution
will occur

Still, what good is that?

Hardy-Weinberg equilibrium model is a
null model
It is a random expectation given a specific
set of assumptions
Specification of those assumptions allows
us to see when and how evolutionary
change does occur

And what about the only two

alleles nonsense?

Non-equilibrium: violations of
Hardy-Weinberg

Mutation
Selection
Migration
Drift
Non-random mating

Pop Quiz
A has frequency of 0.9, what is the
frequency of a (if only two alleles)?
p2 + 2pq + q2=
What are the HW genotypic frequencies?

Hardy-Weinberg recap
If a set of five assumptions is met:
Then, allele frequencies wont change
And,
Genotypic frequencies follow from
p2 + 2pq + q2 = 1

Mutation as an evolutionary Force

Mutation critical for genetic variation
But can mutation, by itself, have much
evolutionary impact on allele frequencies?

A = functional allele; a = mutant

knockout
Mutation from A to a
Mutation rate of 1 per 10,000
plausible but high

Mutation from a to A negligible

Suppose, initially A allele has a frequency
of 0.9

What is the effect of mutation?

Effect over time?

Mutation - selection balance

Mutations are random
In finely tuned organisms, most mutations
are bound to be bad
Bad mutations selected against
Also created anew
Rate of creation by mutation = rate of
removal by selection
Called mutation-selection balance

Deleterious mutations selected

against
How common should any particular
deleterious mutation be?
Depends on how bad (strength of selection)
Depends on how often re-created (mutation
rate)

Is that useful information?

Two examples
Spinal muscular atrophy, study by Wirth et al.
Caused by mutation in telSMN
Telomeric survival motor neuron

Cystic fibrosis, study by Pier et al.

Most common lethal autosomal recessive disease
in Caucasians
Proximate cause bacteria Pseudomonas aeruginosa
lung damage

Spinal muscular atrophy

telSMN knock out mutants frequency of 0.01
Selection coefficient ~ 0.9
Can use equation to estimate what mutation rate
would be needed to counter s = 0.9, and give q^
of 0.01
And the calculated answer is 0.9 X 10-4
mutations per allele per generation
Wirth et al. directly measured rate of 1.1 X 10-4
Mutation-selection balance

Cystic fibrosis
Chromosome 7 mutations for protein called
Cystic fibrosis transmembrane conductance
regulator (CFTR)
Expressed in lining of lungs and intestines
In lungs, enables cells to destroy
Pseudomonas aeruginosa
Until recently most cistic fibrosis sufferers
died before reproducing (i.e. selection very
very strong, approaching s = 1)

Cystic fibrosis mutation-selection

balance?
Could mutation selection balance maintain
mutants at frequency of 0.02 with s = 1?
Yes, but mutation rate would have to be
about 4 X 10-4
Observed mutation rate much lower, ca. 6.7
X 10-7

Does something else maintain

cystic fibrosis causing mutations
at that level?
This is an important question to ask in this
case; note that it was not necessary to ask
this in the case of Spinal Muscular Atrophy
The answer could have important medical
implications

A possible answer
What if mutation(s) favored in another context?
Recall CFTR expressed in intestine as well as
lung
Pier et al hypothesized a function for most
common disease causing allele
Prevents intestinal infection by Salmonella typhi
Agent causes Typhoid fever

DeltaF508 allele, cystic fibrosis,

and Typhoid fever
deltaF508 most common cystic fibrosis
causing allele
In humans, homozygotes would get cystic
fibrosis
Could heterozygotes be protected from
Typhoid fever?

Mouse study
Heterozygotes more
resistant to
Salmonella typhi
Homozygotes almost
completely protected

Pleiotropy and genetic correlation

deltaF508 single allele with multiple
(pleiotropic) effects
Genetic correlation
Lung lining phenotype will show some
similarity to intestine lining phenotype
Not completely separate traits for selection to
act upon independently

And thats what is next: selection

Selection as an evolutionary force

Hardy-Weinberg null model assumptions
Individuals of all genotypes survive at equal
rates, and contribute gametes equally to the
gene pool
Bottom line is differential reproductive
success: some genotypes out reproduce
others

example

Result
7.5% increase in frequency of B1 allele
7.5% decrease in frequency of B2 allele

Population has evolved

Also true for much weaker selection

Selection across generations

Empirical Example: Adh

Alcohol dehydrogenase
Enzyme breaks down ethanol

Cavener & Clegg Drosophila melanogaster

experiment
Two replicate populations on ethanol spiked
food
Two replicate populations on ethanol free food

Tracked allele frequency across time

Adh semi-natural selection experiment

Selection and genotypic frequency

If a set of five assumptions is met:
Then, allele frequencies wont change
And,
Genotypic frequencies follow from
p2 + 2pq + q2 = 1

Does selection alter genotype frequency?

Sometimes, for one generation
Heterozygote advantage

Selection and genotype frequency

Allele freq. 0.5, 0.5
Heterozygotes fitter
After selection
Allele freq. 0.5, 0.5
Predicts genotype
Frequency of
0.25, 0.5, 0.25
Observe 0.167, 0.667,
0.167

Generalizing Selection
Recall development of Hardy-Weinberg
argument
We took special case of A = 0.6 and a = 0.4
Then generalized using p as frequency of the
A allele and q as frequency of the alternative
allele a
Can we develop a general model of selection?

Change in allele frequency

depends on genotypic fitness
Why?, because selection acts on phenotypes
not alleles
Fitness symbolized as w
Fitness of a genotype symbolized with
subscripts, so that
Fitness of A1A1 genotype has fitness w11
Fitness of A1A2 genotype has fitness w12
Fitness of A2A2 genotype has fitness w22

How will allele frequency change

with unequal genotypic fitness?
Unequal fitness needs a standard
Fitness of a genotype is expressed relative
to a standard of the average fitness of all
genotypes

Genotypic frequency change

Genotypic frequency change depends on the
fitness of the genotype relative to the
average fitness

How have allele frequencies changed?

How many A1 gametes produced?
A1 gametes in proportion to A1A1
genotype frequency multiplied by relative
genotype fitness
Plus 1/2 of A1A2 genotype frequency
multiplied by relative genotype fitness
1/2 of 2pq = pq

Same for A2 alleles

A2 gametes proportional to frequency of
A2A2 genotype (q2) multiplied by the relative
fitness of the q2 genotype
Plus 1/2 of the alleles contributed by
heterozygotes
that is, 1/2 of the frequency of heterozygotes (2pq)
multiplied by heterozygote relative fitness
1/2 of 2pq = pq

Allele frequency change

Change = new allele frequency - old allele
frequency

Ta Da!!!
We have made a general expression that
quantitatively describes how allele
frequency will change depending on the
average fitness of that allele
Similarly,

Patterns of Selection
Selection on dominant versus recessive
alleles
Selection on heterozygotes and
homozygotes
Frequency dependent selection

Dominant and recessive alleles

A dominant to a if
AA genotype = A phenotype
AND
Aa genotype = A phenotype
but
aa genotype = a phenotype
If so, A called dominant, a called recessive

Suppose homozygous recessive is

lethal
waa = 0
How will frequency of a change over time?
If a is common?
If a is rare?

If a is common then genotype aa is pretty

common
If frequency of a = q then genotype frequency = q2

What do we expect
If at first a is common, it will decrease
rapidly
As it becomes more rare, it will decrease
more slowly
Because when rare, there are few aa genotypes
with fitness = 0

Data from flour beetles

Dawson started experiment with
heterozygotes, so p = q = 0.5
waa = 0

Data agree with qualitative

prediction
Rapid change when aa genotype common
Slow change when aa genotype rare

Selection against recessive

Selection for recessive

Heterozygotes
Heterozygotes dont always express dominant
phenotype
Heterozygotes can have fitness
Intermediate
Changes rate of evolution, not outcome

Higher
Heterozygote superiority or overdominance

Lower
Heterozygote inferiority or underdominance

Overdominance
Suppose genotypic fitness is as follows:
wAA = 0.735
wAa = 1
waa = 0

Equilibrium frequency of a allele > 0

Example seen in Drosophila melanogaster
study of Muaki and Burdick (1958)
Specific gene effects unknown

Four populations, 2 replicates

Overdominance generalized
Mean fitness across genotypes

underdominance

What if heterozygotes have lower fitness?

Considerably more complicated
Outcome depends on starting conditions
One allele goes to fixation (100%)
Other allele lost

Underdominance generalized

Adaptive landscape

Heterozygote selection outcomes

s and t are selection terms for homozygotes

Both negative = heterozygote superiority (overdominance)
Both positive = heterozygote inferiority (underdominance)

Frequency dependent selection

Strength of selection depends on frequency
For example, if the allele that is rare is
favored
Two examples
Book scale eating fish
Sex

Scale eating fish Perissodus microlepis

Lake Tanganyika
Mouth twisted to side, bites scales off other fish
Left mouth bites right side of victim; Right mouth
bites left; Victim fish wary

Sex
Sex ratio (males:females) usually about 1:1
Imagine the fitness of a male if males were
really rare
That rare male would make lots of babies

Female fitness if females rare?

Most males would not reproduce

Imagine male female controlled by single

locus with two alleles