1. We expect selection to keep lethal recessive alleles low in frequency
What explains these exceptions?
lethal recessive disease
frequency in general population
PKU
1/200,000
Tay Sachs
1/360,000
Sickle Cell
1/125,000
sub-population
frequency
Caucasian
1/10,000
Ashkenazi Jewish
1/3,600
African Americans
1/5000
Reproductive isolation
Founders effect
heterozygote advantage

2. Tay Sachs due to Founders Effect
parent population founders of new population
FF FF FF
FF FF FF
FF FF FF FF Ff FF Ff
Ff = 2/12 = 0.16
Ff = 2/3 = 0.67

3. Sickle cell trait due to Heterozyote Advantageaa Aa AA aa Aa AA
What type of selection?

4. The sickle cell allele results from a single point mutation in the gene coding for hemoglobin
dominant
Negatively
charged
recessive
Hydrophobic

5. With the changed amino acid, in low O2 situations the behavior of the molecule changes
Normal Hb
Mutant Hb
Bonding forms chains
Valine is hydrophobic, so it is ‘pushed’ to other HB molecules, creating chains. These are most problematic when the molecule is carrying little O2.
Polymerization occurs only after red blood cells have released the oxygen molecules that they carry to various tissues throughout the body. Once red blood cells return to the lungs where hemoglobin can bind oxygen, the long fibers of Hb S molecules depolymerize or break apart into single molecules. Cycling between polymerization and depolymerization causes red blood cell membranes to become rigid. The rigidity of these red blood cells and their distorted shape when they are not carrying oxygen can result in blockage of small blood vessels. This blockage can cause episodes of pain and can damage organs.

6. Sickled RBC
Are more likely to burst
Cause flow problems

7. Heterozygote Advantage
Heterozygotes maintain a deleterious allele in a population
These carriers typically do not express the disease
Who are carriers? Which offspring has the disease?

8. Observed: tropical Africa harbors malaria
Most common in Africa:
225million cases
781,000 deaths
Mostly children, under the age of five.
Fact Sheet. Us Global Health Policy. March 2011

9. The distribution of the sickle cell allele and the incidence of malaria are correlated
Yellow = malaria zone
Striped = sickle cell in high frequency
Experiments carried out in vitro with sickle trait red cells showed that under low oxygen tension, cells infected with P. falciparum parasites sickle much more readily than do uninfected cells (Roth Jr., et al., 1978). Since sickle cells are removed from the circulation and destroyed in the spleen, selective sickling of infected sickle trait red cells would reduce the parasite burden in people with sickle trait. These people would be more likely to survive acute malarial infections.

10. Infected cells more readily sickle Aa aa AA
Likely to die from malaria
Dies from sickle cell disease
Infected cells more readily sickle
Sickling kills the parasite (low K+)
Sickled cells removed in immune response
Experiments carried out in vitro with sickle trait red cells showed that under low oxygen tension, cells infected with P. falciparum parasites sickle much more readily than do uninfected cells (Roth Jr., et al., 1978). Since sickle cells are removed from the circulation and destroyed in the spleen, selective sickling of infected sickle trait red cells would reduce the parasite burden in people with sickle trait. These people would be more likely to survive acute malarial infections.

11. Both AA and aa children high risk of death; Aa beats both diseases

12. Sickle Cell trait (Aa) results in greater malaria survival – fewer infected cells, fewer sickled cells

13. Heterozygous
Homozygous
normal RBC
Homozygous sickled

14. PRACTICE
If 9% of an African population is born with sickle-cell disease (ss), what percentage of the population will be more resistant to malaria because they are heterozygous (Ss) for the sickle-cell gene?
Use q2 approach

15. Practice
If 9% of an African population is born with sickle-cell disease (ss), what percentage of the population will be more resistant to malaria because they are heterozygous (Ss) for the sickle-cell gene?
q2= .09
q = .3
p = .7
2pq = 2(.7)(.3) = .42

17. Parasite • Vector • Host
4 species of Plasmodium
Impacts mostly children, under the age of five.
Anopheles mosquito
40 species transmit malaria

18. Global Malaria Eradication Program
WHO 1955
• DDT already available as an agricultural pesticide
• Success dependent upon, temperate climate, seasonal malaria cycle, good healthcare
• Successful eradication on islands : Taiwan, Jamaica

19. Problem : Natural selection
• Reduction often followed by resurgence of now- resistant Anopheles populations
Resistant Anopheles selected for

20. Evidence Conclusion Not possible to eradicate malaria
In tropical areas
A sample of mosquitos was captured at each time indicated
The number killed by a standard dose of DDT in the laboratory was measured.
From Curtis et al. (1978)
how quickly the population evolves!