How multiple alleles are maintained in a population’s gene pool.
Often people think that if an allele offers an advantage over other alleles in the gene pool that it should
be favored by selection, increase in frequency and ultimately replace all of the other alleles in the gene
pool. However, in reality there are a number of mechanisms that can maintain genetic diversity in a
gene pool so that multiple alleles remain over the long term.
For example, you should remember that Dawson’s beetle work shows that recessive deleterious rare
alleles are hard to eliminate from a gene pool because they hide from selection as heterozygotes. This
only applies if the allele is not dominant. Because a dominant allele exerts its effect because it is
expressed both as a heterozygote and a homozygote a dominant allele is always visible to selection.
Ways in which multiple alleles can be maintained in a gene pool
1. Heterozygote advantage -- individuals with copies of two different alleles have highest fitness.
2. Negative frequency dependent selection – the rarer an allele becomes the more it is favored by
selection.
3. 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.
4. Recessive deleterious alleles hide from selection as heterozygotes, which slows their elimination
from the gene pool.
1. Heterozygote Advantage
One way in which multiple alleles may be maintained in a population is through heterozygote advantage
(also called overdominance). The classic example is the sickle cell allele.
Sickle cell anemia
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 and tend to get stuck in
capillaries the narrowest blood vessels in the body. This can lead to tissue and organ damage.
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, which under low oxygen conditions is what causes the red blood cells to become sickle
shaped.
Why isn’t sickle cell allele eliminated by selection? This is because only individuals homozygous for the
allele get sickle cell anemia. Individuals with only one copy of the allele (heterozygotes) get sickle cell
trait (which is a mild form of the disease). Individuals with the sickle cell allele (one or two copies) don’t
get malaria, which is a huge advantage wherever malaria occurs and this results in heterozygotes having
higher survival than either homozygote. This is called 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 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.
The opposite of heterozygote advantage is when heterozygotes have lower fitness than homozygotes.
This is also called underdominance. In this situation one or other allele will go to fixation, but which
depends on the starting allele frequencies so underdominance does not maintain genetic diversity.
Frequency-dependent selection
In some cases the costs and benefits of a trait depend on how common it is in a population. Under
positive frequency-dependent selection, the commoner a phenotype is the more successful it is.
Hence, if two phenotypes are determined by single alleles one allele will go to fixation and the other be
lost, but which one is lost depends on the starting frequencies.
An example of positive frequency dependent selection—flat snails. 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. Positve frequency dependent selection thus favors the
elimination of the rarer allele.
2. Negative frequency dependent selection
Under negative frequency-dependent selection a trait is increasingly favored the rarer it becomes. This
naturally tends to maintain genetic diversity just because rareness increases fitness. As an allele get less
common its fitness goes up, which leads to the allele becoming more common. As a result of negative
frequency dependence multiple alleles are maintained in the genepool.
An example of negative frequency dependent selection-Elderflower orchids
A color polymorphism occurs in Elderflower Orchids. There are two flower colors: yellow and purple.
Neither color offers a food reward to bees. As a result a bee that visits a flower gets no reward from
doing so and tends to switch to a different color flower for its next visit. This leads to bees alternating
their visits to different colored flowers. colors.
How are two colors maintained in the population? Gigord et al. hypothesisized that bees tend to visit
equal numbers of each flower color so the rarer color will have advantage (will get more visits from
pollinators). They experimentally tested this by providing five arrays of potted orchids each with a
different frequency of yellow orchids in it. The researchers monitored the orchids for fruit set and
removal of pollinaria (pollen bearing structures), which are both good indicators of fitness. As predicted,
the reproductive success of yellow flowers varied with frequency. The rarer the yellow flower was the
higher its fitness.
3. Mutation-selection balance
Most mutations are deleterious and natural selection acts to remove such deleterious alleles from
populations. Deleterious alleles sometimes persist, however, because mutation continually produces
them. When the rate at which deleterious alleles being eliminated is equal to their rate of production by
mutation we have mutation-selection balance.
The 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.
The 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.
Examples of mutation selection balance.
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. The frequency of the allele
therefore is accounted for by observed mutation rate.
Is frequency of Cystic fibrosis maintained by mutation selection balance?
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.
There is very strong selection against CF alleles, but CF frequency is about 0.02 in Europeans.
Can mutation rate account for high frequency?
Assume selection coefficient (s) of 1 and q = 0.02. Using these figures we get an estimated mutation
rate µ of 4.0 X 10-4
But the actual mutation rate is only 6.7 X 10-7 [about a thousand times lower than the estimated]
Is there an alternative explanation? There may be heterozygote advantage in which individuals with one
copy of the normal (or wild-type allele) and one copy of the CF allele have higher fitness..
Pier et al. (1998) hypothesized CF heterozygotes may be resistant to typhoid fever. Typhoid fever is
caused by Salmonella typhi bacteria. These bacteria infiltrate gut by crossing epithelial cells. Pier et al.
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 their cell
surface.
They carried out an experimental test in which they produced mouse cells with three different CFTR
genotypes
CFTR homozygote (wild type)
CFTR/F508 heterozygote (F508 most common CF mutant allele)
F508/F508 homozygote
They exposed the cells to S. typhi bacteria and measured number of bacteria that entered cells. The
results were clear.
The F508/F508 homozygote was almost totally resistant to S. typhi and the wild type homozygote
highly vulnerable. Heterozygotes contained 86% fewer bacteria than wild type.
Further support for idea the F508 allele provides resistance to typhoid provided by positive
relationship between F508 allele frequency in generation after typhoid outbreak and severity of the
outbreak. (see graph below).