Chapter 6 part 4 Maintaining allelic diversity

Dawson’s beetle work shows that
deleterious rare alleles may be very hard
to eliminate from a gene pool because
they remain hidden from selection as
This only applies if the allele is not
dominant. A dominant allele is
expressed both as a heterozygote and a
homozygote and so is always visible to
One way in which multiple alleles may
be maintained in a population is through
heterozygote advantage (also called
Classic example is sickle cell allele.
Sickle cell anemia is a condition
common among West Africans and
those of West African descent.
Under low oxygen conditions the red
blood corpuscles are sickle shaped.
Untreated the condition usually causes
death in childhood.
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
 Sickle cell homozygotes die of sickle cell
anemia, many “normal” homozygotes
die of malaria.
 Stabilizing selection thus favors sickle cell
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
In some cases the costs and benefits of a
trait depend on how common it is in a
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
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
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
As predicted, reproductive success of
yellow varied with frequency.
5.21 a
Most mutations are deleterious and natural
selection acts to remove them from
Deleterious alleles persist, however,
because mutation continually produces
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
 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
Can mutation rate account for high
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
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
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
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
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 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
Example: Female is daughter of two halfsiblings.
Two ways female could receive alleles
that are identical by descent.
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
In humans, children of first cousins have
higher mortality rates than children of
unrelated individuals.
Each dot on
rates for a
Fig 6.28
Mortality rate
for children
of cousins
about 4%
higher than
rate for
children of
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
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 (16611700) 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.

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