Balancing selection, sickle cell anemia, and the African slave trade as an evolutionary test of...

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Dan GraurUniversity of Houston

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Genotype A1A1 A1A2 A2A2

Fitness w11 w12 > w11,w22 w22

Frequency p2 2pq q2

Overdominance

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Genotype A1A1 A1A2 A2A2

Fitness w11 w12 < w11,w22 w22

Frequency p2 2pq q2

Underdominance

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The change in the frequency of A2 from generation to generation is:

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At equilibrium, i.e., when ∆q = 0.

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overdominance underdominance

s = 0.04 and t = 0.02 s = - 0.02 and t = - 0.01

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Overdominant selection is inherently inefficient, even if the two homozygotes are not viable.

Powderpuff Chinese Crested

Veryexpensivedog

Cheap dog; mostly discarded

aaAa

AA

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The peculiar case of sickle-cell anemia

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10Glutamic acid Valine

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mvhltpeeksavtalwgkvnvdevggealgrllvvypwtqrffesfgdlstpdavmgnpkvkahgkkvlgafsdglahldnlkgtfatlselhcdklhvdpenfrllgnvlvcvlahhfgkeftppvqaayqkvvagvanalahkyh 147aa

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mvhltpveksavtalwgkvnvdevggealgrllvvypwtqrffesfgdlstpdavmgnpkvkahgkkvlgafsdglahldnlkgtfatlselhcdklhvdpenfrllgnvlvcvlahhfgkeftppvqaayqkvvagvanalahkyh 147aa

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“sticky” b globin

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Pleiotropic effects

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normal fitness

somewhat reduced fitness

reduced fitness

Intuitive Model: Directional Selection

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In theory, the end result should have been directional selection — a

drastic reduction in HS

allele frequency in the population.

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In practice, the frequency of the

HS allele may

reach enormous values in some populations.

>20%

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Worldwide distribution of sickle-cell anemia

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Plasmodium falciparum

How to test the hypothesis that sickle cell anemia is under

balancing selection by using a the African slave trade as an

evolutionary experiment

26An evolutionary “experiment”: Slave trade

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Surinamendemic malaria

HS frequency = 20%

Curaçauno malaria

HS frequency = 5%

West Africa Frequency >20%

300 years = 10-15 generations

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• With malaria in the background, heterozygotes have a huge advantage over the wild type homozygotes.• In the absence of malaria, the heterozygotes have a slight disadvantage in comparison to wild type homozygotes. • The fitness of the HsHs homozygotes is not affected by the presence or absence of malaria.

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Modiano D, Luoni G, Sirima BS, Simpore J, Verra F, Konate A, Rastrelli E, Olivieri A, Calissano C, Paganotti GM, D'Urbano L, Sanou I, Sawadogo A, Modiano G, Coluzzi M. 2001. Haemoglobin C protects against clinical Plasmodium falciparum malaria. Nature 414:305-308.

A newly discovered allele that protects against malaria but does

not have deleterious effects in homozygotes

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codonposition

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Glutamic acid Lysine

Hemoglobin CE to V = HS

E to K = HC

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In the long term and in the presence of malaria, allele HbC is expected to replace alelle HbS in central West Africa.