2. Sickle Cell Anemia

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

4. 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.

5. Location of the HBB Gene: Chromosome 11 Location of the HBB Gene: Chromosome 11 Chromosome Map From: http://www.ncbi.nlm.nih.gov/mapview/maps.cgi?ORG=hum&CHR=11&MAPS=ideogr%5B11pter%3A11qter%5D,loc%5B0.000000%3A142127415.000000% 5D&query=e:HBB

6. Normal Hemoglobin  Globin  Tetramer  Protein with 4 subunits  Heme  One per subunit  Has an iron atom  Carries O 2  Found in red blood cells

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

8. 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 O 2 HB A1C HB S Change in Protein Structure

9. 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

10. Shape causes problems

11. Red blood cells Going through Vessels

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

13. 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  Excessive thirst  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 * About 30% of Jamaican patients with Sickle Cell develop ulcers in comparison to 1% of Americans

14. 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 x-ray of a hand swollen from dactylitis An enlarged and unhealthy spleen from someone with Sickle Cell

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

16. Prevalence o It is estimated the up to 80,000 people in America have Sickle Cell Disease o 1/500 African Americans have Sickle Cell Disease o 1/1000 -4000 Hispanics have Sickle Cell o 1/12 African Americans are carriers for Sickle Cell o 1/50 Asians are carriers for Sickle Cell o 1/100 Greeks are carriers for Sickle Cell

17. Sickle cell frequency  High frequency of heterozygotes  1 in 5 in Central Africans = H b H s  This is unusual for allele with severe detrimental effects in homozygotes  1 in 100 = H s H s  usually die before reproductive age

18. QUESTION??? Why is the H s allele maintained at such high levels in African populations?

19. Patterns of Natural Selection  Genes provide the source of variation.  The environment selects for the best adapted phenotype. (Natural Selection)  An allele is only common where it will provide an advantage. (Natural Selection) beneficial  Mutations can be neutral, harmful or beneficial 1. Harmful mutations result in dysfunctional proteins, they occur frequently but they are selected against and remain rare. allow the cell to produce a new or improved protein 2. 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.

20. QUESTION??? Is there some selective advantage of being heterozygous… H b H s

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

22. Plasmodium

23. 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.

24. 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.

25. 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.

26. Heterozygote Advantage  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 Hypothesis: In malaria-infected cells, the O 2 level is lowered e n ough to cause sickling which kills the cell & destroys the parasite. Hypothesis: In malaria-infected cells, the O 2 level is lowered e n ough to cause sickling which kills the cell & destroys the parasite.

27. 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.

28. Heterozygote Advantage  In tropical Africa, where malaria is common:  homozygous dominant (normal)  reduced survival or reproduction from malaria: H b H b  homozygous recessive  reduced survival & reproduction from sickle cell anemia: H s H s  heterozygote carriers  survival & reproductive advantage: H b H s Frequency of sickle cell allele & distribution of malaria