maintaining multiple alleles in gene pool

Maintaining multiple alleles in gene pool

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.

Ways in which multiple allelesare 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

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.

Sickle cell anemia

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.

Why isn’t sickle cell allele eliminated by selection?

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.

Heterozygote advantage

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.

Heterozygote advantage

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 (heterozygote disadvantage)

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

Frequency-dependent selection

In some cases the costs and benefits of a trait depend on how common it is in a population.

Positive frequency-dependent selection

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.

Positive frequency-dependent selection

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.

Negative frequency-dependent selection

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

Mutation-selection balance

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.


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.

Cystic fibrosis

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

Cystic fibrosis

Is there an alternative explanation?

Cystic fibrosis

Cystic fibrosis

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.

Cystic fibrosis

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.

Cystic fibrosis

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

Cystic fibrosis

Exposed cells to S. typhi bacteria.

Measured number of bacteria that entered cells.

Clear results

Fig 5.27a

Cystic fibrosis

F508/F508 homozygote almost totally resistant to S. typhi.

Wild type homozygote highly vulnerable

Heterozygote contained 86% fewer bacteria than wild type.

Cystic fibrosis

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

Non-Random mating

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.

Inbreeding

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?

Inbreeding

In each generation the proportion of heterozygous individuals in the population will decline.

Inbreeding in California Sea Otters

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.

General analysis of inbreeding

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 half-siblings.

Two ways female could receive alleles that are identical by descent.

Fig 6.27a

Male Female Male

Female Male

Half-sibling mating

Fig 6.27b


Total probability of scenario is 1/16 + 1/16 = 1/8.

Inbreeding exposes deleterious alleles to selection

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.

Fig 6.28

Each dot on graphrepresents mortalityrates for a humanpopulation.

Mortality rate for children of cousinsconsistently about 4%higher than rate forchildren of non-relatives.

Inbreeding effects on high blood pressure

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.

Inbreeding in royal families

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’s-1700’s)

Extensive intermarriage of close Hapsburg relatives occurred.


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

http://en.wikipedia.org/wiki/Charles_II_of_Spain

maintaining multiple alleles in gene pool

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