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 selectionas heterzygotesslows 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?
Negative frequency-dependent selection • 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.
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.
Mutation-selection balance • 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.
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?
Cystic fibrosis • 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 • 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
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.