1. Pedigrees and Sickle-cell Anemia

2. Why use Pedigrees? Punnett squares work well for organisms that have large numbers of offspring and controlled matings, but humans are quite different: 1. Small families - Even large human families have 20 or fewer children. 2. Uncontrolled matings, often with heterozygotes.

3. Goals of Pedigree Analysis 1. Determine the mode of inheritance: dominant, recessive, sex-linked, autosomal, mitochondrial. 2. Determine the probability of an affected offspring for a given cross.

4. Basic Symbols

5. More Symbols Fraternal Twins Identical Twins

6. Try and figure out the method of inheritance… X-linked recessive

7. Try and figure out the method of inheritance… Autosomal recessive

8. Try and figure out the method of inheritance… X-linked recessive

9. Try and figure out the method of inheritance… Autosomal dominant

10. Pedigrees and Sickle-cell Anemia

11. Case Study: Sickle Cell Anemia One of the most common genetic diseases that afflicts persons of African ancestry. –about 10% of such persons carry the allele for this trait –in some areas of Africa, upwards of 40% carry the allele Homozygous individuals with sickle-cell disease suffer from: –“Crises” in joints and bones –Strokes, blindness –Damage to lungs, kidneys or heart

12. Case Study: Sickle Cell Anemia Untreated, many sufferers die before the age of 20 –Modern medical treatments can prolong life to age 40-50 (for individuals who are homozygous for Sickle cell anemia) Normal allele (A) and Sickle allele (S) are CODOMINANT –In heterozygous individuals (AS), both normal and abnormal hemoglobin are produced –Individuals are usually healthy, but may notice problem in conditions of low oxygen (high altitude) –Known as ‘carriers’

13. Normal red blood cellsSickled red blood cells Sickle Cell Disease What does it actually do? –Affects the structure of hemoglobin Help bind oxygen in blood, carry to body cells Hemoglobin becomes ‘sticky’, and red blood cells collapse when there is no oxygen

14. Red Blood Cell Oxygen molecule Hemoglobin subunit Hemoglobin

15. Hemoglobin gene Chromosome 11 Chromosomal location of Hemoglobin

16. Sequence of normal hemoglobin DNA:CTGACTCCTGAGGAGAAGTCT GACTGAGGACTCCTCTTCAGA Amino acids: Sequence found in sickling hemoglobin DNA:CTGACTCCTGTGGAGAAGTCT GACTGAGGACACCTCTTCAGA Amino acids: Mutation found in Hemoglobin

17. Sequence of normal hemoglobin DNA:CTGACTCCTGAGGAGAAGTCT GACTGAGGACTCCTCTTCAGA Amino acids: L T P E E K S Sequence found in sickling hemoglobin DNA:CTGACTCCTGTGGAGAAGTCT GACTGAGGACACCTCTTCAGA Amino acids: L T P V E K S Mutation found in Hemoglobin

18. Normal hemoglobin Sickle Cell hemoglobin No oxygen No Oxygen: stuck together No Oxygen: Separate No Oxygen Sickle Cell Hemoglobins Stick Together

19. CTGACTCCTGTGGAGAAGTCT GACTGAGGACACCTCTTCAGA L T P E E K S L T P V E K S CTGACTCCTGAGGAGAAGTCT GACTGAGGACTCCTCTTCAGA DNA order of amino acids protein shape cell function Effects of Sickle Cell Mutation

20. High frequency of Malaria causing microbe % of population that has HbS (Sickle Cell mutation) Frequency of Sickle Cell Causing Mutation vs. Frequency of Malaria Causing Microbe Africa

21. Case Study: Sickle Cell Anemia Why do we see this more often in Africa, especially when it is deadly? –There must be a benefit to having this abnormal allele! Malaria! –Caused by a blood parasite –Infect red blood cells –When a blood cell with defective hemoglobin are infected, the cells sickle and die The parasite is trapped and infection is reduced