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| | CCR5-Δ32 deletion allele and sickle cell trait 22.09.15 Larissa von Buol & Salome Bechtler 1 Polymorphism and disease resistance

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Page 1: Polymorphism and disease resistance · Bubonic plague vs. smallpox ! Model description ! Dominant vs. incomplete dominace ! ... Evaluating plague and smallpox as historical selective

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CCR5-Δ32 deletion allele and sickle cell trait

22.09.15 Larissa von Buol & Salome Bechtler 1

Polymorphism and disease resistance

Page 2: Polymorphism and disease resistance · Bubonic plague vs. smallpox ! Model description ! Dominant vs. incomplete dominace ! ... Evaluating plague and smallpox as historical selective

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§  Mechanism and distribution

§  Bubonic plague vs. smallpox

§  Model description

§  Dominant vs. incomplete dominace

§  Discussion

22.09.15 Larissa von Buol & Salome Bechtler 2

Agenda: CCR5-Δ32 deletion allele

Page 3: Polymorphism and disease resistance · Bubonic plague vs. smallpox ! Model description ! Dominant vs. incomplete dominace ! ... Evaluating plague and smallpox as historical selective

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22.09.15 Larissa von Buol & Salome Bechtler 3

CCR5-receptor and HIV-1

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Page 4: Polymorphism and disease resistance · Bubonic plague vs. smallpox ! Model description ! Dominant vs. incomplete dominace ! ... Evaluating plague and smallpox as historical selective

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22.09.15 Larissa von Buol & Salome Bechtler 4

Distribution of the allele

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Page 5: Polymorphism and disease resistance · Bubonic plague vs. smallpox ! Model description ! Dominant vs. incomplete dominace ! ... Evaluating plague and smallpox as historical selective

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§  Ca. 1350-1750

§  Affects all ages

§  Episodic occurence with high death rates (15-40% of population)

§  Transmission by rodents

22.09.15 Larissa von Buol & Salome Bechtler 5

Bubonic plague

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Page 6: Polymorphism and disease resistance · Bubonic plague vs. smallpox ! Model description ! Dominant vs. incomplete dominace ! ... Evaluating plague and smallpox as historical selective

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§  Until1978 §  Affects mainly children

§  More continuous, 5 year peaks (30% case fatality)

§  Transmission between humans

22.09.15 Larissa von Buol & Salome Bechtler 6

Smallpox

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Page 7: Polymorphism and disease resistance · Bubonic plague vs. smallpox ! Model description ! Dominant vs. incomplete dominace ! ... Evaluating plague and smallpox as historical selective

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§  Temporal disease patterns §  Age specific nature of disease §  Plague: upper mortality estimates §  Smallpox: 30% case fatality §  Erradication:

§  Plague: 1750 §  Smallpox: 1978

§  s = the average selection coefficient per generation acting on the resistance allele

§  Time period: 700 years (28 generations)

22.09.15 Larissa von Buol & Salome Bechtler 7

Modell description

Page 8: Polymorphism and disease resistance · Bubonic plague vs. smallpox ! Model description ! Dominant vs. incomplete dominace ! ... Evaluating plague and smallpox as historical selective

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22.09.15 Larissa von Buol & Salome Bechtler 8

Dominance: plague

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Page 9: Polymorphism and disease resistance · Bubonic plague vs. smallpox ! Model description ! Dominant vs. incomplete dominace ! ... Evaluating plague and smallpox as historical selective

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22.09.15 Larissa von Buol & Salome Bechtler 9

Dominance: smallpox

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Page 10: Polymorphism and disease resistance · Bubonic plague vs. smallpox ! Model description ! Dominant vs. incomplete dominace ! ... Evaluating plague and smallpox as historical selective

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§  Heterozygotes have 50% protection

§  Plague: s = 0.09

§  Smallpox s = 0.17

§  Smallpox would need 1135 years

22.09.15 Larissa von Buol & Salome Bechtler 10

Incomplete dominance

Page 11: Polymorphism and disease resistance · Bubonic plague vs. smallpox ! Model description ! Dominant vs. incomplete dominace ! ... Evaluating plague and smallpox as historical selective

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§  Smallpox affects younger people (reproductive potential!)

§  Smallpox existed until 1978 (start of AIDS)

§  HIV and poxvirus: disease similarities

§  Geographical distribution

22.09.15 Larissa von Buol & Salome Bechtler 11

Discussion

Page 12: Polymorphism and disease resistance · Bubonic plague vs. smallpox ! Model description ! Dominant vs. incomplete dominace ! ... Evaluating plague and smallpox as historical selective

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22.09.15 Larissa von Buol & Salome Bechtler 12

Distribution of the allele

Page 13: Polymorphism and disease resistance · Bubonic plague vs. smallpox ! Model description ! Dominant vs. incomplete dominace ! ... Evaluating plague and smallpox as historical selective

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§  Sickle-Cell anaemia §  Malaria §  Relation between Malaria and Sickle-cell Trait

§  Observation

§  Discussion

22.09.15 Larissa von Buol & Salome Bechtler 13

Agenda: Sickle cell trait

Page 14: Polymorphism and disease resistance · Bubonic plague vs. smallpox ! Model description ! Dominant vs. incomplete dominace ! ... Evaluating plague and smallpox as historical selective

| | 22.09.15 Larissa von Buol & Salome Bechtler 14

Sickle-Cell anemia

•  Hereditary blood disorder

•  Abnormality in the oxygen-carrying haemoglobin molecule in RBCs

•  Abnormal, sickle-like shape à Various acute and chronic complications

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Page 15: Polymorphism and disease resistance · Bubonic plague vs. smallpox ! Model description ! Dominant vs. incomplete dominace ! ... Evaluating plague and smallpox as historical selective

| | 22.09.15 Larissa von Buol & Salome Bechtler 15

Malaria

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•  Mosquito-borne infectious disease

•  Female Anopheles mosquito •  Parasitic protozoans (Plasmodium)

à Fever, fatigue, vomiting, headaches

Page 16: Polymorphism and disease resistance · Bubonic plague vs. smallpox ! Model description ! Dominant vs. incomplete dominace ! ... Evaluating plague and smallpox as historical selective

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Beet (1946) 102 sicklers à 10 (9,8%) showing malaria parasites 491 non-sicklers à 75 (15,3%) showing malaria parasites à Statistically highly significant

22.09.15 Larissa von Buol & Salome Bechtler 16

Relation between Malaria and Sickle-cell Trait

Page 17: Polymorphism and disease resistance · Bubonic plague vs. smallpox ! Model description ! Dominant vs. incomplete dominace ! ... Evaluating plague and smallpox as historical selective

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22.09.15 Larissa von Buol & Salome Bechtler 17

Observation 1

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Page 18: Polymorphism and disease resistance · Bubonic plague vs. smallpox ! Model description ! Dominant vs. incomplete dominace ! ... Evaluating plague and smallpox as historical selective

| | 22.09.15 Larissa von Buol & Salome Bechtler 18

Observation 2

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Page 19: Polymorphism and disease resistance · Bubonic plague vs. smallpox ! Model description ! Dominant vs. incomplete dominace ! ... Evaluating plague and smallpox as historical selective

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§  Individuals with the Sickle-cell trait suffer from malaria less often and less severely than those without the trait

§  Polymorphism: heterozygote has an advantage over either homozygote

22.09.15 Larissa von Buol & Salome Bechtler 19

Discussion

Page 20: Polymorphism and disease resistance · Bubonic plague vs. smallpox ! Model description ! Dominant vs. incomplete dominace ! ... Evaluating plague and smallpox as historical selective

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§  Allison, A. (1954). Protection afforded by sickle-cell trait against subtertian malarial infection. The Basis of sensation.

§  Franklin Bunn, H. (2015). The triumph of good over evil: protection by the sickle gene against malaria. Perspectives.

§  Galvani, A. & Slatkin, M. (2003). Evaluating plague and smallpox as historical selective pressures for the CCR5- Δ32 HIV-resistance allele. PNAS.

§  https://en.wikipedia.org/wiki/HIV, 18.09.15 §  https://en.wikipedia.org/wiki/Malaria, 20.09.2015 §  https://en.wikipedia.org/wiki/Sickle-cell_disease, 20.09.2015

22.09.15 Larissa von Buol & Salome Bechtler 20

Sources

Page 21: Polymorphism and disease resistance · Bubonic plague vs. smallpox ! Model description ! Dominant vs. incomplete dominace ! ... Evaluating plague and smallpox as historical selective

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§  Img. 1:http://www.hindawi.com/journals/isrn/2013/728392/fig2/, 18.09.15 §  Img. 2: Galvani, A. et al. (2005). The Geographic spread of the CCR5- Δ32 HIV resistance allele. PLOS.

§  Img. 3: http://yourstory.com/2014/07/bubonic-plague/, 19.09.15 §  Img. 4: https://en.wikipedia.org/wiki/Smallpox, 19.09.15 §  Img. 5 & 6: Galvani, A. & Slatkin, M. (2003). Evaluating plague and

smallpox as historical selective pressures for the CCR5- Δ32 HIV-resistance allele. PNAS.

§  Img. 7: https://en.wikipedia.org/wiki/Sickle-cell_disease ,19.09.2015 §  Img. 8: http://rstb.royalsocietypublishing.org/content/366/1579/2806 ,

20.09.2015 §  Img. 9,10: Allison, A. (1954). Protection afforded by sickle-cell trait

against subtertian malarial infection. The Basis of sensation.

22.09.15 Larissa von Buol & Salome Bechtler 21

Sources: Images