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

2. With the changed amino acid the behavior of the molecule in water changes as well, creating polymers
Hb s
Hb a
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.

3. It’s the low O2 SBC that experience the sickling

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

5. HETEROZYGOTE ADVANTAGE
Heterozygous parents
HETEROZYGOTE ADVANTAGE
Heterozygotes maintain a deleterious allele in a population
These carriers typically do not express the disease
Sickle cell
disease

6. HETEROZYGOTE ADVANTAGE
Malaria is caused by plasmodium, a genus of parasitic protists
Mosquitos and humans are plasmodium vectors
The plasmodium parasite that causes malaria is transmitted from mosquitos to men. The parasites spend part of their life cycle in the mosquito and part of it in the human host (Figure 1). The infective plasmodial sporozoites enter the bloodstream from the saliva of the feeding female anopheles mosquito. The Kupfer cells of the liver clear the sporozoites from the blood stream and kill many of the organisms. A fraction of the sporozoites escape destruction however, and penetrate the hepatocytes where they take up residence.
Sickle hemoglobin provides the best example of a change in the hemoglobin molecule that impairs malaria growth and development. The initial hints of a relationship between the two came with the realization that the geographical distribution of the gene for hemoglobin S and the distribution of malaria in Africa virtually overlap. A further hint came with the observation that peoples indigenous to the highland regions of the continent did not display the high expression of the sickle hemoglobin gene like their lowland neighbors in the malaria belts. Malaria does not occur in the cooler, drier climates of the highlands in the tropical and subtropical regions of the world. Neither does the gene for sickle hemoglobin.
Sickle trait provides a survival advantage over people with normal hemoglobin in regions where malaria is endemic. Sickle cell trait provides neither absolute protection nor invulnerability to the disease. Rather, people (and particularly children) infected with P. falciparum are more likely to survive the acute illness if they have sickle cell trait.
people with two genes encoding normal hemoglobin A (designated by red). These people have a significant chance of dying of acute malarial infection in childhood. In contrast, people with two genes for sickle hemoglobin (shown in green) are likely to succumb to sickle cell disease at an early age, as shown in the right-hand side of the figure.
In the center are people with sickle cell trait who possess one gene for normal hemoglobin and one gene for sickle hemoglobin. These children are more likely to survive their initial acute malarial attacks than are people with two genes for normal hemoglobin.
The precise mechanism by which sickle cell trait imparts resistance to malaria is unknown. A number of factors likely are involved and contribute in varying degrees to the defense against malaria.
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 reticuloendothelial system, 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.

7. The distribution of the sickle cell alllele and the incidence of malaria are correlated
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 reticuloendothelial system, 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.
The heterozygote has its few sickled and plasmodium-infected cells destroyed, therefore the child survives

9. 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?

10. 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