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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.

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chapter 8 evolution at multiple loci
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.
slide2
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
slide4
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).
slide5
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.
slide6
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.
example
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
slide8
If studying only locus A or locus B we would conclude populations were identical.
  • However, populations not identical when we look at haplotypes.
slide11
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
slide12
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.
slide14
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.
conditions for linkage equilibrium
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.
conditions for linkage equilibrium1
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.)
coefficient of linkage disequilibrium
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.
what creates linkage disequilibrium in populations
What creates linkage disequilibrium in populations?
  • Three mechanisms:
  • Selection on multilocus genotypes.
  • Genetic drift
  • Population mixing
selection on multilocus genotypes
Selection on multilocus genotypes.
  • Scenario: Locus A and locus B in linkage equilibrium. Gametes combine at random to from zygotes.
selection on multilocus genotypes1
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.
selection on multilocus genotypes2
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
genetic drift
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.
genetic drift followed by selection
Genetic drift followed by selection
  • If selection favors a and its frequency increases, degree of linkage disequilibrium increases too.
slide29

After mutation

and selection

population mixing
Population mixing
  • If two populations, which are in linkage equilibrium, are merged the resulting population may not be in linkage equilibrium.
what eliminates linkage disequilibrium from population
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.
genetic recombination
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.
empirical example of genetic recombination
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.
empirical example of genetic recombination1
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.
empirical example of genetic recombination2
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.
practical reasons to measure linkage disequilibrium
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
reconstructing history of the ccr5 32 locus
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.
reconstructing history of the ccr5 32 locus1
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.
reconstructing history of the ccr5 32 locus2
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.
reconstructing history of the ccr5 32 locus3
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.
reconstructing history of the ccr5 32 locus4
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.
reconstructing history of the ccr5 32 locus5
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.
reconstructing history of the ccr5 32 locus6
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)
reconstructing history of the ccr5 32 locus7
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.
using linkage disequilibrium to detect strong positive selection
Using linkage disequilibrium to detect strong positive selection.
  • A new mutant allele will be in linkage disequilibrium when it first appears. If it persists, it may increase in frequency.
  • Over time linkage disequilibrium will break down as a result of recombination from crossing over.
  • Linkage disequilibrium breaks down fastest for loci further apart on a chromosome because crossing over take place more often between distant loci.
using linkage disequilibrium to detect strong positive selection1
Using linkage disequilibrium to detect strong positive selection.
  • High linkage disequilibrium indicates an allele originated recently.
  • Also, expect a recently mutated allele to be rare unless selection strongly favors it.
using linkage disequilibrium to detect strong positive selection2
Using linkage disequilibrium to detect strong positive selection.
  • If an allele is common, but has high linkage disequilibrium, especially with loci that are located far away on the chromosome, this suggests that the allele has been strongly selected for and must have originated recently.
  • If the allele had arisen a long time ago, sex should have eliminated the linkage disequilibrium.
using linkage disequilibrium to detect positive selection
Using linkage disequilibrium to detect positive selection.
  • An allele of G6PD (Glucose-6-phosphate dehydrogenase), G6PD-202A has a high frequency (~18% in African populations) and has a high degree of linkage disequilibrium.
  • Thus, it appears to have been strongly selected for recently.
g6pd and malaria
G6PD and malaria
  • There are many common G6PD deficiencies and their distribution corresponds closely with the distribution of malaria.
  • Appears that G6PD-202A confers strong protection against malaria.
adaptive significance of sex
Adaptive significance of sex
  • Many risks and costs associated with sexual reproduction.
  • Searching for a mate requires time and energy and exposes organisms to predators.
  • Mate may require investment (food, territory, defense).
  • Risk of sexually transmitted disease.
adaptive significance of sex1
Adaptive significance of sex
  • Why not reproduce asexually?
  • Many organisms can reproduce both sexually and asexually.
  • E.g. plants, aphids.
adaptive significance of sex2
Adaptive significance of sex
  • In populations that can reproduce both asexually and sexually will one mode of reproduction replace the other?
adaptive significance of sex3
Adaptive significance of sex
  • John Maynard Smith explored the question.
  • Considered population in which some organisms reproduce asexually and the others sexually.
  • Made 2 assumptions.
maynard smith s assumptions
Maynard Smith’s assumptions
  • 1. Mode of reproduction does not affect number of offspring she can produce.
  • 2. Mode of reproduction does not affect probability offspring will survive.
  • (asexually reproducing organisms produce only females, sexually reproducing produce both males and females.)
adaptive significance of sex4
Adaptive significance of sex
  • Asexually reproducing females under Maynard Smith’s assumptions leave twice as many grandchildren as sexually reproducing females.
  • This is because each generation of sexually reproducing organisms contains only 50% females.
adaptive significance of sex5
Adaptive significance of sex
  • Ultimately, asexual reproduction should take over.
  • However, in nature this is not the case.
  • Most organisms reproduce sexually and both sexual and asexual modes of reproduction are used in many organisms
adaptive significance of sex6
Adaptive significance of sex
  • Sex must confer benefits that overcome the mathematical reproductive advantage of asexual reproduction.
  • One or both of Maynard Smith’s assumptions must be incorrect.
adaptive significance of sex7
Adaptive significance of sex
  • Assumption 1 (mode of reproduction does not affect number of offspring she can produce) is violated in species where males helps females (humans, birds, many mammals, some fish).
  • However, not likely a general explanation because in most species male does not help.
adaptive significance of sex8
Adaptive significance of sex
  • Most likely advantage of sex is that it increases offspring’s prospects of survival.
dunbrack et al 1995 experiment
Dunbrack et al. (1995) experiment
  • Lab populations of flour beetles
  • Mixed populations of red and black strains.
  • Strains designated as “sexual” or “asexual” in experimental replicates.
dunbrack et al 1995 experiment1
Dunbrack et al. (1995) experiment
  • Asexual strain in culture. Every generation each adult replaced by 3 new individuals from reservoir population of sexual strain. This simulates a 3X reproductive advantage, but there is no evolution in response to the environment.
  • Sexual strain allowed to breed and remain in culture. Could evolve.
dunbrack et al 1995 experiment2
Dunbrack et al. (1995) experiment
  • Two strains prevented from breeding with each other.
  • Populations tracked for 30 generations.
  • 8 replicates in experiment. Four different concentrations of malathion (insecticide).
  • Controls: No evolution, but one strain had 3x reproductive advantage.
dunbrack et al 1995 experiment3
Dunbrack et al. (1995) experiment
  • Control results.
  • “Asexually” reproducing strain outcompeted the sexually reproducing strain.
dunbrack et al 1995 experiment4
Dunbrack et al. (1995) experiment
  • Experimental cultures: Initially asexual strain increased in frequency, but eventually sexual strain took over.
  • Rate at which sexual strain took over was proportional to malathion concentration.
dunbrack et al 1995 experiment5
Dunbrack et al. (1995) experiment
  • Conclusion: Assumption 2 of Maynard Smith’s null model is incorrect.
  • Descendants produced by sexual reproduction achieve higher fitness than those produced asexually.
sex in populations means genetic recombination
Sex in populations means genetic recombination
  • Sex involves:
    • Meiosis with crossing over
    • Matings with random individuals
    • Random meeting of sperm and eggs
    • Consequence is genetic recombination. New combinations of genes brought together each generation.
why is sex beneficial
Why is sex beneficial?
  • 1. Genetic drift plus mutation make sex beneficial. Escapes Muller’s ratchet.
  • 2. Selection imposed by changing environments makes sex beneficial
genetic drift plus mutation muller s ratchet
Genetic drift plus mutation: Muller’s ratchet
  • An asexually reproducing female will pass a deleterious mutation to all her offspring.
  • Back mutation only way to eliminate it.
  • Muller’s ratchet: accumulation of deleterious alleles in asexually reproducing populations.
muller s ratchet
Muller’s ratchet
  • Small, asexually reproducing population.
  • Deleterious mutations occur occasionally.
  • Mutations selected against.
  • Population contains groups of individuals with zero, one, two, etc. mutations.
muller s ratchet1
Muller’s ratchet
  • Few individuals in each group. If by chance no individual with zero mutations reproduces in a generation, then the zero mutation group is lost.
  • Rate of loss of groups by drift will be higher than rate of back mutation so population will over time accumulate deleterious mutations in a ratchet fashion.
muller s ratchet2
Muller’s ratchet
  • Burden of increased number of deleterious mutations (genetic load) may eventually cause population to go extinct.
  • Sexual reproduction breaks ratchet. E.g. two individuals each with one copy of a deleterious mutation will produce 25% of offspring that are mutation free.
anderson and hughes 1996 test of muller s ratchet in bacteria
Anderson and Hughes (1996) test of Muller’s ratchet in bacteria.
  • Propagated multiple generations of bacterium, but each generation derived from one individual (genetic drift).
  • 444 cultures. At end of experiment (2 months) 1% of cultures had reduced fitness (lower than wild-type bacteria), none had increased fitness. Results consistent with Muller’s ratchet.
selection favors sex in changing environments
Selection favors sex in changing environments.
  • Effects of Muller’s ratchet are slow and take many generations to affect asexually reproducing populations.
  • However, advantage of sex is apparent in only a few generations. What short-term benefit does sex provide?
selection favors sex in changing environments1
Selection favors sex in changing environments.
  • In constant environments asexual reproduction is a good strategy (if mother is adapted to environment, offspring will be too).
  • However, if environment changes, offspring may be poorly adapted and all will be poorly adapted because they are identical.
selection favors sex in changing environments2
Selection favors sex in changing environments.
  • Sexually reproducing females produce variable offspring so if the environment changes some may be well adapted to the new environment.
selection favors sex in changing environments3
Selection favors sex in changing environments.
  • Red Queen Hypothesis: evolutionary arms race between hosts and parasites.
  • (Red Queen runs to stand still)
  • Parasites and hosts are in a perpetual struggle. Host evolving defenses, parasite evolving ways to evade them.
  • Different multilocus host genotypes are favored each generation. Sex creates the genotypes.
do parasites favor sex in hosts
Do parasites favor sex in hosts?
  • Lively (1992) studied New Zealand freshwater snail. Host to parasitic trematodes.
  • Trematodes eat host’s gonads and castrate it! Strong selection pressure.
  • Snail populations contain both obligate sexually and asexually reproducing females.
do parasites favor sex in hosts1
Do parasites favor sex in hosts?
  • Proportion of sexual vs asexual females varies from population to population.
  • Frequency of trematode infections varies also.
do parasites favor sex in hosts2
Do parasites favor sex in hosts?
  • If evolutionary arms race favors sex, then sexually reproducing snails should be commoner in populations with high rates of trematode infections.
  • Results match prediction.
slide98

White slice indicates

frequency of males

and thus sexual

reproduction

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