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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 . - PowerPoint PPT Presentation
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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.
Maintaining multiple alleles in gene pool
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.
Maintaining multiple alleles in 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.
Negative frequency-dependent selection
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).
Negative frequency-dependent selection
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)
Negative frequency-dependent selection
As predicted, reproductive success of yellow varied with frequency.
Negative frequency-dependent selection
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.
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.
Mutation-selection balance
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.
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
Mutation-selection balance
Observed mutation rate is about 1.1 X10-4, very close agreement in estimates.
High frequency of allele accounted for by observed mutation rate.
Mutation-selection balance
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.
Inbreeding in California Sea Otters
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.
Inbreeding in California Sea Otters
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)
Inbreeding in California Sea Otters
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
Inbreeding in California Sea Otters
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
Inbreeding in California Sea Otters
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.
General analysis of inbreeding
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.
General analysis of inbreeding
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.
General analysis of inbreeding
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
General analysis of inbreeding
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.
Inbreeding in royal families
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.
Inbreeding in royal families
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