1. Sickle Cell Anemia

2. Introduction Hereditary disease Blood disorder
Mutation in the Hemoglobin Beta Gene
Found on chromosome 11
Causes abnormally shaped red blood cells
A normal red blood cell is shaped as a round donut
Sickle cell has a shape like a sickle or a “ C “ form

3. Hemoglobin Gene The HBB gene codes for the protein hemoglobin
Hemoglobin contains iron and transports oxygen from the lungs to the peripheral tissues.
The HBB protein is 146 amino acids long.
The HBB gene is found on chromosome 11.

4. Location of the HBB Gene: Chromosome 11
Chromosome Map From:

5. Normal Hemoglobin Globin Tetramer Protein with 4 subunits Heme
One per subunit
Has an iron atom
Carries O2
Found in red blood cells

6. It starts with MUTATION
dominant
Negatively
charged
recessive
Hydrophobic
The sickle cell allele results from a single point mutation in the gene coding for hemoglobin

7. Change in Protein Structure
HB A1C
HB S
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.
Because valine is hydrophobic, it is “pushed” to the other HB molecules. This behavior creates polymers. It happens mostly when the molecule is carrying little O2

8. Change in Shape
Polymerization occurs after the RBCs have released their oxygen molecules
When the RBC returns to the lungs and oxygen is bound, the HB depolymerizes.
This back and forth change causes the RBC membrane to become rigid
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.

9. Shape causes problems

10. Red blood cells Going through Vessels

11. Pleotropy A singe gene influences more than one phenotypic trait.
Genes that exert effects on multiple aspects of physiology or anatomy are pleiotropic

12. Symptoms of Sickle Cell
Abdominal and bone/joint pain
Breathlessness
Delayed growth and puberty
Fatigue and fever
Jaundice (yellowed skin)
Paleness
Rapid heart rate
Greater risk for infection
Adolescents and adults can develop ulcers on their legs
Chest pain
Poor eyesight, blindness – when blood can’t get to the back of eyes, they don’t have a constant nourishment, causing people to not be able to see
Excessive thirst
* About 30% of Jamaican patients with Sickle Cell develop ulcers in comparison to 1% of Americans

13. Diseases and Conditions people with Sickle Cell are likely to develop:
Acute chest syndrome
Aplastic crisis
Dactylitis – swelling of the hands and feet
Painful crises: really painful episodes when blood cells are blocked from going to certain parts of the body – pain can occur anywhere, but it is usually in the chest, arms, and legs
Enlarged spleen – sickle cells pool in the spleen, and in some cases there is no spleen in the body.
Stroke
Hematuria
An enlarged and unhealthy spleen from someone with Sickle Cell
An x-ray of a hand swollen from dactylitis

14. Peripheral Blood Smears
Why isn’t the mutant sickle cell gene eliminated by natural selection?

15. Prevalence
It is estimated the up to 80,000 people in America have Sickle Cell Disease
1/500 African Americans have Sickle Cell Disease
1/ Hispanics have Sickle Cell
1/12 African Americans are carriers for Sickle Cell
1/50 Asians are carriers for Sickle Cell
1/100 Greeks are carriers for Sickle Cell

16. Sickle cell frequency High frequency of heterozygotes
1 in 5 in Central Africans = HbHs
This is unusual for allele with severe detrimental effects in homozygotes
1 in 100 = HsHs
usually die before reproductive age
Sickle Cell:
In tropical Africa, where malaria is common, the sickle-cell allele is both an advantage & disadvantage. Reduces infection by malaria parasite.
Cystic fibrosis:
Cystic fibrosis carriers are thought to be more resistant to cholera:
1:25, or 4% of Caucasians are carriers Cc

17. QUESTION???
Why is the Hs allele maintained at such high levels in African populations?

18. Patterns of Natural Selection
Genes provide the source of variation.
The environment selects for the best adapted phenotype.
An allele is only common where it will provide an advantage. (Natural Selection)
Mutations can be neutral, harmful or beneficial
Harmful mutations result in dysfunctional proteins, they occur frequently but they are selected against and remain rare.
Beneficial mutations allow the cell to produce a new or improved protein and gives the individual a selective advantage. They are rare, but are selected for and become more common over time.

19. QUESTION???
Is there some selective advantage of being heterozygous… HbHs

20. Sickle cell and malaria
Distribution of the sickle cell allele
Distribution of Malaria
As you can see, the areas where Malaria is present and the Sickle Cell allele is present are overlapping.

21. Plasmodium

22. Malaria Prognosis
Malaria is one of the planet's deadliest diseases and one of the leading causes of sickness and death in the developing world.

23. According to the World Health Organization
300 to 500 million clinical cases of malaria each year
1.5 to 2.7 million deaths.
Children aged one to four are the most vulnerable to infection and death.

24. According to the World Health Organization
Malaria kills more than one million children - 2,800 per day - each year in Africa alone.
In regions of intense transmission, 40% of toddlers may die of acute malaria
Malaria is responsible for as many as half the deaths of African children under the age of five.

25. Heterozygote Advantage
Hypothesis:
In malaria-infected cells, the O2 level is lowered enough to cause sickling which kills the cell & destroys the parasite.
The recessive sickle-cell allele produces hemoglobin with reduced capacity to carry oxygen
This mutation also confers malaria resistance in heterozygotes
This heterozygote advantage leads to a larger proportion of the recessive allele than usual in areas where malaria is widespread
These populations exhibit balanced polymorphism between the mutant and wild-type alleles

26. An Experiment on Sickle Cell and Malaria in 2005
There were over 1000 people chosen from Kenya, which is a place where Malaria is very prominent
The doctor performing the study, Dr. Tom Williams, found that the protection to Malaria from having the Sickle Cell trait rose from 20% in the first two years of life to 50% and over by the age of 10.
His theory of the resistance of people with sickle cell trait results from the immune system building a defense.

27. Heterozygote Advantage
In tropical Africa, where malaria is common:
homozygous dominant (normal)
reduced survival or reproduction from malaria: HbHb
homozygous recessive
reduced survival & reproduction from sickle cell anemia: HsHs
heterozygote carriers
survival & reproductive advantage: HbHs
Frequency of sickle cell allele & distribution of malaria