Transcript mutation-selection balance.


Dawson’s beetle work shows recessive
deleterious rare alleles are hard to
eliminate from a gene pool because
they hide from selection as
heterozygotes.

However, a dominant allele is expressed
both as a heterozygote and as a
homozygote and so is always visible to
selection.

Selection acts to remove deleterious
alleles

However, there are many ways in which
multiple alleles of a gene can be
maintained in a population.
› Heterozygote advantage -- individuals with copies of two
different alleles have highest fitness.
› Negative frequency dependent selection – the rarer an
allele becomes the more it is favored by selection.
› Mutation-selection balance – a high mutation rate
produces new copies of alleles at a high enough rate to
maintain an allele despite selection against it.
› Recessive deleterious alleles hide from selection as
heterzygotes slows their elimination from the gene pool.

Heterozygote advantage (also called
overdominance).

Classic example is sickle cell allele.

Sickle cell anemia, a disease that causes
early death, is common among West
Africans and descendants .

Under low oxygen conditions the red
blood corpuscles are sickle shaped.

About 1% of West Africans have sickle
cell anemia.

A single mutation causes a valine amino
acid to replace a glutamine in the alpha
chain of hemoglobin.

The mutation causes hemoglobin
molecules to stick together.
Only individuals homozygous for the
allele get sickle cell anemia.
 Individuals with only one copy of the
allele (heterozygotes) get sickle cell trait
(a mild form of the disease)
 Individuals with the sickle cell allele (one
or two copies) don’t get malaria.

Heterozygotes have higher survival than
either homozygote (heterozygote
advantage).
 Sickle cell homozygotes die of sickle cell
anemia, many “normal” homozygotes
die of malaria.
 Stabilizing selection thus favors sickle cell
allele.


A heterozygote advantage (or
overdominance) results in a balanced
polymorphism in a population.

Both alleles are maintained in the
population as the heterozygote is the
best combination of alleles and a purely
heterozygous population is not possible.

Underdominance is when the
heterozygote has lower fitness than
either homozygote.

This situation is In this case one or other
allele will go to fixation, but which
depends on the starting allele
frequencies

In some cases the costs and benefits of a
trait depend on how common it is in a
population.

In this case the commoner a phenotype
is the more successful it is.

If two phenotypes are determined by
single alleles one allele will go to fixation
and the other be lost, but which one
depends on the starting frequencies.

In “flat” snails individuals mate face to
face and physical constraints mean only
individuals whose shells coil in the same
direction can mate successfully.

Higher frequencies of one coil direction
leads to more mating for that phenotype
and eventually it replaces the other
types.

Under negative frequency-dependent
selection a trait is increasingly favored
the rarer it becomes.

Color polymorphism in Elderflower Orchid

Two flower colors: yellow and purple.
Offer no food reward to bees. Bees
alternate visits to colors.

How are two colors maintained in the
population?

Gigord et al. hypothesis: Bees tend to
visit equal numbers of each flower color
so rarer color will have advantage (will
get more visits from pollinators).

Experiment: provided five arrays of
potted orchids with different frequencies
of yellow orchids in each.

Monitored orchids for fruit set and
removal of pollinaria (pollen bearing
structures)

As predicted, reproductive success of
yellow varied with frequency.
5.21 a

Most mutations are deleterious and natural
selection acts to remove them from
populations.

Deleterious alleles persist, however,
because mutation continually produces
them.

When rate at which deleterious alleles being
eliminated is equal to their rate of production
by mutation we have mutation-
selection balance.

Equilibrium frequency of deleterious allele q
= square root of µ/s where µ is mutation rate
and s is the selection coefficient (measure of
strength of selection against allele; ranges
from 0 to 1).

See Box 6.6 for derivation of equation.

Equation makes intuitive sense.

If s is small (mutation only mildly deleterious)
and µ (mutation rate) is high than q (allele
frequency) will also be relatively high.

If s is large and µ is low, than q will be low too.
Spinal muscular atrophy is a generally lethal
condition caused by a mutation on
chromosome 5.
 Selection coefficient estimated at 0.9.
Deleterious allele frequency about 0.01 in
Caucasians.
 Inserting above numbers into equation and
solving for µ get estimated mutation rate of
0.9 X 10-4

Observed mutation rate is about 1.1 X10-4,
very close agreement in estimates.
 High frequency of allele accounted for by
observed mutation rate.


Cystic fibrosis is caused by a loss of function
mutation at locus on chromosome 7 that
codes for CFTR protein (cell surface protein
in lungs and intestines).

Major function of protein is to destroy
Pseudomonas aeruginosa bacteria.
Bacterium causes severe lung infections in
CF patients.

Very strong selection against CF alleles,
but CF frequency about 0.02 in
Europeans.

Can mutation rate account for high
frequency?

Assume selection coefficient (s) of 1 and
q = 0.02.

Estimate mutation rate µ is 4.0 X 10-4

But actual mutation rate is only 6.7 X 10-7

Is there an alternative explanation?

May be heterozygote advantage.

Pier et al. (1998) hypothesized CF
heterozygotes may be resistant to typhoid
fever.

Typhoid fever caused by Salmonella typhi
bacteria. Bacteria infiltrate gut by crossing
epithelial cells.

Hypothesized that S. typhi bacteria may
use CFTR protein to enter cells.

If so, CF-heterozygotes should be less
vulnerable to S. typhi because their gut
epithilial cells have fewer CFTR proteins
on cell surface.
Experimental test.
 Produced mouse cells with three
different CFTR genotypes
 CFTR homozygote (wild type)
 CFTR/F508 heterozygote (F508 most
common CF mutant allele)
 F508/F508 homozygote


Exposed cells to S. typhi bacteria.

Measured number of bacteria that
entered cells.

Clear results
Fig 5.27a

F508/F508 homozygote almost totally
resistant to S. typhi.

Wild type homozygote highly vulnerable

Heterozygote contained 86% fewer
bacteria than wild type.

Further support for idea F508 provides
resistance to typhoid provided by
positive relationship between F508
allele frequency in generation after
typhoid outbreak and severity of the
outbreak.
Fig 5.27b
Data from 11 European countries

Another assumption of Hardy-Weinberg
is that random mating takes place.

The most common form of non-random
mating is inbreeding which occurs when
close relatives mate with each other.

Most extreme form of inbreeding is self
fertilization.

In a population of self fertilizing organisms all
homozygotes will produce only
homozygous offspring. Heterozygotes will
produce offspring 50% of which will be
homozygous and 50% heterozygous.

How will this affect the frequency of
heterozygotes each generation?

In each generation the proportion of
heterozygous individuals in the
population will decline.

Because inbreeding produces an excess
of homozygotes in a population,
deviations from Hardy-Weinberg
expectations can be used to detect
such inbreeding in wild populations.

Sea otters once abundant along the west
coast of the U.S were almost wiped out by
fur hunters in the 18th and 19th centuries.

California population reached a low of 50
individuals (now over 1,500). As a result of
this bottleneck the population has less
genetic diversity than it once had.

Population still at a low density and
Lidicker and McCollum (1997)
investigated whether this resulted in
inbreeding.

Determined genotypes of 33 otters for
PAP locus, which has two alleles S (slow)
and F (fast)

The genotypes of the 33 otters were:
› SS 16
› SF 7
› FF 10

This gives approximate allele frequencies
of S= 0.6 and F = 0.4

If otter population in H-W equilibrium,
genotype frequencies should be
› SS = 0.6* 0.6 = 0.36
› SF =2*0.6*0.4 = 0.48
› FF = 0.4*0.4 = 0.16

However actual frequencies were:
› SS= 0.485, SF= 0.212, FF =0.303

There are more homozygotes and fewer
heterozygotes than expected for a random
mating population.

Having considered alternative explanations
for deficit of heterozygotes Lidicker and
McCollum (1997) concluded that sea otter
populations show evidence of inbreedng.

Self-fertilization and sibling mating most
extreme forms of inbreeding, but matings
between more distant relatives (e.g.
cousins) has same effect on frequency
of homozygotes, but rate is slower.

F = Coefficient of inbreeding: probability
that two alleles in an individual are
identical by descent (both alleles are
copies of a particular ancestor’s allele in
some previous generation).

F increases as relatedness increases.

If we compare heterozygosity of an inbred
population Hf with that of a random mating
population Ho relationship is

Hf = Ho (1-F)

Anytime F>0 frequency of heterozygotes is
reduced and frequency of homozygotes
naturally increases.

Calculating F. Need to use pedigree
diagrams.

Example: Female is daughter of two halfsiblings.

Two ways female could receive alleles
that are identical by descent.
Male
Female
Female
Male
Male
Fig 6.27a
Half-sibling mating
Fig 6.27b

Total probability of scenario is 1/16 + 1/16
= 1/8.

Inbreeding increases frequency of
homozygotes and thus the probability
that deleterious alleles are visible to
selection.

In humans, children of first cousins have
higher mortality rates than children of
unrelated individuals.
Each dot on
graph
represents
mortality
rates for a
human
population.
Fig 6.28
Mortality rate
for children
of cousins
consistently
about 4%
higher than
rate for
children of
non-relatives.

In a study of 2760 individuals from 25
Croatian islands Rudan et al. found a
strong positive relationship between high
blood pressure and the inbreeding
coefficent.

Royal families have been particularly
prone to inbreeding.

In Ancient Egypt because royal women
were considered to carry the royal
bloodline the pharaoh routinely was
married to a sister or half-sister.

The most famous example of a genetic
disorder exacerbated by inbreeding is
the Hapsburg jaw or Hapsburg lip [severe
lower jaw protrusion] .

(Hapsburgs were the ruling family of
Austria and Spain for much of the 1400’s1700’s)

The last of the Spanish Hapsburgs, Charles II
(1661-1700) had such severe jaw protrusion
he could not chew his food properly.

Charles II also had a large number of other
recessively inherited genetic problems that
caused physical, mental, sexual and other
problems. Charles was infertile and the last
of the Spanish Hapsburg kings.
http://en.wikipedia.org/wiki/Charles_II_of_Spain