Chapter 8: Evolution at multiple loci

1. Chapter 8: Evolution at multiple loci • Evolution at two loci: Linkage equilibrium and linkage disequilibrium. • Locus is location on a chromosome where a gene occurs. • Single locus Hardy-Weinberg models are simple. However, many traits are controlled by combined influence of many genes.

2. Pair of loci located on same chromosome. • (Recall locus is location on chromosome of a gene). • Gene at locus A has two alleles A and a • Gene at locus B has two alleles B and b

4. In two-locus Hardy-Weinberg analysis we track allele and chromosome frequencies. • Thus 4 possible chromosome genotypes: • AB, Ab, aB, ab • Multilocus genotype referred to as a haplotype (from haploid genotype).

5. Does selection on locus A affect our ability to make predictions about evolution at locus B? • Sometimes. Depends on whether loci are in linkage equilibrium or linkage disequilibrium.

6. Two loci in a population are in linkageequilibrium when genotype of a chromosome at one locus is independent of the genotype at the other locus on the same chromosome. • I.e. knowing genotype at one locus is of no use in predicting genotype at the other locus.

7. Example • Two hypothetical populations each containing 25 chromosomes. • Allele frequencies are identical in both populations. • A = 0.6, a = 0.4; B = 0.8, b = 0.2

8. If studying only locus A or locus B we would conclude populations were identical. • However, populations not identical when we look at haplotypes.

11. Population 1 Population 2 • AB = 0.48 AB = 0.44 • Ab = 0.12 Ab = 0.16 • aB = 0.32 aB = 0.36 • ab = 0.08 ab = 0.04

12. Population 1 is in linkage equilibrium. • Frequency of B on chromosomes carrying A is 12/15 or 0.8, frequency of B on chromosomes carrying a is 8/10 or 0.8. • Frequency of B is same on chromosomes carrying A as on chromosomes carrying a.

14. Population 2 is in linkage disequilibrium. • Frequency of B on chromosomes carrying A is 11/15 or 0.73, frequency of B on chromosomes carrying a is 9/10 or 0.9.

16. Conditions for linkage equilibrium • 1. Frequency of B on chromosomes carrying allele A is equal to frequency of B on chromosomes carrying allele a. • 2. Frequency of a chromosome haplotype can be calculated by multiplying frequencies of constituent alleles, i.e. frequency of AB is = freq. A X freq. B.

17. Conditions for linkage equilibrium • 3. Coefficient of linkage disequilibrium (D) is equal to zero. See Box 8.1 and satisfy yourself that the equation below makes sense. • D = gABgab - gAbgaB • (gAB = frequency of chromosome AB, etc.)

18. Coefficient of linkage disequilibrium • D can range from - 0.25 to 0.25. • 0.25 when AB and ab only genotypes and both at frequency of 0.5 • Similarly -0.25 when Ab and aB only genotypes and both at frequency of 0.5 • If D = 0, then population in linkage equilibrium and value of D is a measure of the degree of linkage disequilibrium.

19. What creates linkage disequilibrium in populations? • Three mechanisms: • Selection on multilocus genotypes. • Genetic drift • Population mixing

20. Selection on multilocus genotypes. • Scenario: Locus A and locus B in linkage equilibrium. Gametes combine at random to from zygotes.

22. Selection on multilocus genotypes. • Assume genotype ab/ab is of size 10 units. • For all other genotypes every copy of A or B adds one unit of size (e.g. Ab/aB is size 12). • Assume predators eat all genotypes of < 13 units size.

24. Selection on multilocus genotypes. • Survivors (65.3% of population) in linkage disequilibrium by all 3 criteria because some genotypes missing. • E.g. criterion 3: D= gABgab - gAbgaB • D = 0.4416*0 - (0.0576*0.1536) = - 0.0088

25. Genetic drift • Scenario: Small population with two genotypes AB and Ab. No copies of allele a. • Single Ab chromosome mutation converts an A to an a. This single ab chromosome puts population in linkage disequilibrium. • Scenario is drift because only in a small population would you expect to have only a single mutation of A to a. In large population you would expect many mutations of A to a and a to A.

26. Before mutation

27. Genetic drift followed by selection • If selection favors a and its frequency increases, degree of linkage disequilibrium increases too.

28. After mutation

29. After mutation and selection

30. Population mixing • If two populations, which are in linkage equilibrium, are merged the resulting population may not be in linkage equilibrium.

32. What eliminates linkage disequilibrium from population? • Sexual reproduction steadily reduces linkage disequilibrium. • Crossing over during meiosis breaks up old combinations of alleles and creates new combinations.

33. Genetic recombination • Genetic recombination tends to randomize genotypes in relation to other genotypes (i.e., it reduces linkage disequilibrium.) • Rate of decline in linkage disequilibrium is proportional to rate of recombination.

34. r is recombination rate, r is related to how far apart two loci are on a chromosome.

35. Empirical example of genetic recombination • Clegg et al. (1980) established two fruit fly populations that were in linkage disequilibrium. • Population 1 AB and ab each 0.5 frequency. • Population 2 aB and Ab each 0.5 frequency.

36. Empirical example of genetic recombination • Populations of about 1,000 individuals maintained for 48-50 generations. • Flies allowed to mate freely. • Populations sampled every 1-2 generations to count frequencies of 4 haplotypes.

38. Empirical example of genetic recombination • Crossing-over created missing haplotypes in each population and linkage disequilibrium disappeared. • In general, in random-mating populations sex is efficient enough at eliminating linkage disequilibrium that most alleles are in linkage equilibrium most of the time.

39. Practical reasons to measure linkage disequilibrium • There are two major uses of measures of linkage disequilibrium. • Can be used to reconstruct history of genes and populations • Can be used to identify alleles recently favored by positive selection

40. Reconstructing history of the CCR5-Δ32 locus • Where did the CCR5-Δ32 allele come from and when did it originate? • CCR5-Δ32 is the allele that provides a selective advantage against HIV.

41. Reconstructing history of the CCR5-Δ32 locus • CCR5-Δ32 is located on chromosome 3 and near two short-tandem repeat sites called GAAT and AFMB. • GAAT and AFMB are non-coding and have no effect on fitness. Both GAAT and AFMB have a number of different alleles.

42. Reconstructing history of the CCR5-Δ32 locus • Stephens et al. (1998) examined haplotypes of 192 Europeans. • Found that GAAT and AFMB alleles in close to linkage equilibrium with each other.

44. Reconstructing history of the CCR5-Δ32 locus • However, CCR5 is in strong linkage disequilibrium with both GAAT and AFMB. • Almost all chromosomes carrying CCR5-Δ32 also carry allele 197 at GAAT and allele 215 at AFMB.

47. Reconstructing history of the CCR5-Δ32 locus • Most likely reason for observed linkage disequilibrium is genetic drift. • Hypothesis: in past was originally only one CCR5 allele the CCR5+ allele, a mutation on a chromosome with the haplotype CCR5--GAAT-197--AFMB-215 created the CCR5Δ32 allele.

48. Reconstructing history of the CCR5-Δ32 locus • The CCR5Δ32 allele was favored by selection and rose to high frequency dragging the other two alleles with it. • Since its appearance and spread, crossing over and mutation have been breaking down the linkage disequilibrium. Now about 15% of Δ32-197-215 haplotypes have changed to other haplotypes.

49. Reconstructing history of the CCR5-Δ32 locus • Based on rates of crossing over and mutation rates, Stephens et al. (1998) estimate the CCR5-Δ32 allele first appeared about 700 years ago (range of estimates 275-1875 years)

50. Reconstructing history of the CCR5-Δ32 locus • Because the CCR5-Δ32 increased in frequency so rapidly selection must have been strong. • Most obvious candidate is an epidemic disease. • Myxoma virus a relative of smallpox uses CCR5 protein on cell surface to enter host cell, which suggests the epidemic disease that favored CCR5-Δ32 may have been smallpox. • However, timing of origin also closely matches period of bubonic plague.