1. One change. Multiple origins. How can you deduce such a thing? 1

2. Pop quiz ❖ What is the leading cause of death of humankind, summed over everything, ever? 2

3. How you die 3 ❖If drugs are not available or if the parasites are resistant to them, malaria infection can develop to anemia, hypoglycemia or cerebral malaria, in which capillaries carrying blood to the brain are blocked. ❖Cerebral malaria can cause coma, life-long-learning disabilities, and death. http://www.malarianomore.org/pages/what-is- malaria

4. off topic? Malaria (mala aria = ‘bad air’) Plasmodium falciparum Apparently, we got it from chimps* we got it from chimpswe got it from chimps Plasmodium falciparum Apparently, we got it from chimps* we got it from chimpswe got it from chimps Image Source: http://www.sanger.ac.uk/PostGenomics/plasmodium/presentations/plasmodium_lifecycle.shtml 4 Note the mosquito!

5. http://www.worldmapper.org/images/largepng/389. png Where malaria does its killing 5

6. Hypotheses... Source: http://anthro.palomar.edu/synthetic/synth_4.htm MalariaSickle alleles 6 Correlation is obvious. Why might the incidence of sickle alleles track incidence of malaria?

7. a Fly in the Ointment ❖ Nucleotide: A => T ❖ Amino acid: Glu => Val ❖ Hemoglobin: free => sticky ❖ Person: healthy => anemic Image: Fig 7.3, Genetics: analysis of genes and genomes (D. Hartl and E. W. Jones) 7

8. Questions/review ❖ How many ways are there to fail in the making of brown stuff in the eye? [be blue eyed] ❖ How many ways are there to fail to turn off your lactase (milk- sugar digesting) gene after toddlerhood? [be lactose tolerant] ❖ How many ways are there to have a glutamic acid @ codon 6 of beta-hemoglobin? [let’s consider single nte. changes only] 8

9. Not an ideal solution, but a common one How could we deduce independent origins? 9

10. Another view of linkage 10 ❖ What do you observe happening over successive meioses? ❖ What do you observe not happening? ❖ What are the consequences for regions of DNA adjacent to the black circle? ❖ Conclusion: it’s not nucleotides, but regions of DNA that are little boats traveling down the generations. ❖ A small boat (short sequence) is only very rarely re-built

11. Inferences 11 * *

12. What’s in a distance ❖ “centimorgan”: span of nucleotides with likelihood of a recombination event occurring once per 100 generations ❖ In humans, it’s ca. 1,000,000 nucleotides ❖ In other words, point A and point B can be MILLIONS of nucleotides away and not get separated for many generations in humans 12

13. Today’s ref 13 “A novel sickle cell mutation of yet another origin in Africa: the Cameroon type C. Lapoumeroulie et al. Human Genetics 89: 333-7 (1992)

14. Changes 14

15. “A plague upon both your houses” —spoken by Mercutio, Romeo and Juliet, in response to… being killed 15

16. Sickle cell anemia ❖ Homozygote for Val6 die without treatment, ignore malaria ❖ Cool fact: can treat by turning fetal hemoglobin back on ❖ Heterezygotes are OK & resist malaria ❖ Homozygote of Glu6 healthy, susceptible to malaria 16

17. Another way ❖ The product of the ‘duffy’ gene is on the surface of RBCs ❖ The malaria protozoan attaches here ❖ “Fy(a+b+): 49% Caucasians, 1% African Americans, 9% Chinese Fy(a-b+): 34% Caucasians, 22% African Americans, <1% Chinese Fy(a-b+): 17% Caucasians, 9% African Americans, 91% Chinese Fy(a-b-): 0% Caucasian, 68% African Americans*, 0% Chinese ❖ There are trade-offs in susceptibility to other diseases, including cancer 17 Source: http://en.wikipedia.org/wiki/Duffy_antigen_system http://en.wikipedia.org/wiki/Duffy_antigen_system * >90% of West African blacks

18. Cystic Fibrosis & CFTR ❖ Chloride channel—helps sweat and ‘lubricate’ b/c water follows the Cl- ions out ❖ Great thing in hot weather ❖ In the cold, not as essential… ❖ and can be over-triggered by dysentery diseases ❖ appears that heterozygotes may be more resistant 18

19. FYI: Cycle of fevers & infection 19 ❖ Malaria is a febrile, mosquito-borne infection, classically characterized by periodic chills, rigors, and high fevers followed by profuse sweating, which occur at regular intervals of 48 to 72 hours. Infection in humans begins when the infected female anopheline mosquito injects the sporozoite parasitic form from its salivary glands into the bloodstream during a blood meal. The sporozoites are carried to the liver, where they undergo asexual. When these infected liver cells burst, merozoites are released into the blood, where they invade red blood cells. The intraerythrocytic parasite develops through ring forms into schizonts that produce more infectious merozoites that affect additional red cells. The periodic fever is the result of synchronization of red cell lysis and release of more merozoites. Some of the organisms develop into distinct sexual forms (gametocytes) which, if ingested by the Anopheles mosquito during a feeding, can undergo sexual reproduction that starts the cycle over again. http://malaria.jhsph.edu/about_malari a/