Maintaining multiple alleles in gene pool

1. 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.

2. 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.

3. 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.

4. Maintaining multiple alleles in gene pool • Heterozygote advantage (also called overdominance). • Classic example is sickle cell allele.

5. 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.

7. 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.

9. 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.

12. 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.

13. 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.

15. 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

17. Frequency-dependent selection • In some cases the costs and benefits of a trait depend on how common it is in a population.

18. 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.

20. 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.

22. Negative frequency-dependent selection • Under negative frequency-dependent selection a trait is increasingly favored the rarer it becomes.

24. 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?

25. 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).

26. 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)

27. Negative frequency-dependent selection • As predicted, reproductive success of yellow varied with frequency.

28. 5.21 a

29. 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.

30. 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.

31. 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.

32. 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.

33. 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

34. 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.

35. 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.

36. Cystic fibrosis • Very strong selection against CF alleles, but CF frequency about 0.02 in Europeans. • Can mutation rate account for high frequency?

37. 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

38. Cystic fibrosis • Is there an alternative explanation?

39. 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.

40. 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.

41. 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

42. Cystic fibrosis • Exposed cells to S. typhi bacteria. • Measured number of bacteria that entered cells. • Clear results

43. Fig 5.27a

44. Cystic fibrosis • F508/F508 homozygote almost totally resistant to S. typhi. • Wild type homozygote highly vulnerable • Heterozygote contained 86% fewer bacteria than wild type.

45. 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.

46. Fig 5.27b Data from 11 European countries

47. 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.

48. 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?

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