One change.One change.Multiple origins.Multiple origins.

How can you deduce such a thing?How can you deduce such a thing?

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Pop quiz

❖ What is the leading cause of death of humankind, What is the leading cause of death of humankind, summed over everything, ever?summed over everything, ever?

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How you die3

❖ • 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

off topic? Malaria (mala aria = ‘bad air’)

Plasmodium Plasmodium falciparumfalciparum

Apparently, Apparently, we got it from chimpswe got it from chimps**

Plasmodium Plasmodium falciparumfalciparum

Apparently, Apparently, we got it from chimpswe got it from chimps**

Image Source: http://www.sanger.ac.uk/PostGenomics/plasmodium/presentations/plasmodium_lifecycle.shtml

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Note the mosquito!

http://www.worldmapper.org/images/largepng/389.png

Where malaria does its killing

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Hypotheses...

Source: http://anthro.palomar.edu/synthetic/synth_4.htm

Malaria

Sickle alleles

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Correlation is obvious. Why might the incidence of sickle alleles track incidence

of malaria?

a Fly in the Ointment❖ Nucleotide: Nucleotide: AA => => TT

❖ Amino acid: Amino acid: GluGlu => => ValVal

❖ Hemoglobin: Hemoglobin: freefree => => stickysticky

❖ Person: Person: healthyhealthy => => anemicanemic

Image: Fig 7.3, Genetics: analysis of genes and genomes (D. Hartl and E. W. Jones)

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Questions/review❖ How many ways are there to How many ways are there to fail fail in the making of brown in the making of brown

stuff in the eye? [be blue eyed]stuff in the eye? [be blue eyed]

❖ How many ways are there to How many ways are there to failfail to turn off your lactase to turn off your lactase (milk-sugar digesting) gene after toddlerhood? [be (milk-sugar digesting) gene after toddlerhood? [be lactose lactose toleranttolerant]]

❖ How many ways are there to have a glutamic acid @ How many ways are there to have a glutamic acid @ codon 6 of beta-hemoglobin? [let’s consider single nte. codon 6 of beta-hemoglobin? [let’s consider single nte. changes only]changes only]

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Not an ideal solution, but a common one

How could we deduce independent origins?

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Another view of linkage10

❖ What do you observe happening over successive What do you observe happening over successive meioses?meioses?

❖ What do you observe What do you observe notnot happening? happening?

❖ What are the consequences for regions of DNA What are the consequences for regions of DNA adjacent toadjacent to the black circle? the black circle?

❖ Conclusion: it’s not Conclusion: it’s not nucleotidesnucleotides, but regions of DNA , but regions of DNA that are little boats traveling down the generations. that are little boats traveling down the generations.

❖ A small boat (short sequence) is only very rarely re-A small boat (short sequence) is only very rarely re-builtbuilt

Inferences11

*

*

What’s in a distance

❖ ““centimorgan”: span of nucleotides with likelihood of a centimorgan”: span of nucleotides with likelihood of a recombination event occurring recombination event occurring onceonce per per 100100 generationsgenerations

❖ In humans, it’s ca. In humans, it’s ca. 1,000,0001,000,000 nucleotides nucleotides

❖ In other wordsIn other words, point A and point B can be MILLIONS , point A and point B can be MILLIONS of nucleotides away and not get separated for of nucleotides away and not get separated for many many generations in humansgenerations in humans

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Today’s ref13

“A novel sickle cell mutation of yet another origin in Africa: the Cameroon type

C. Lapoumeroulie et al. Human Genetics 89: 333-7 (1992)

Changes14

““A plague upon both A plague upon both your houses”your houses”

——spoken by Mercutio, spoken by Mercutio, Romeo and JulietRomeo and Juliet, in , in response to… being killedresponse to… being killed

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Sickle cell anemia

❖ Homozygote for Val6 die without treatment, ignore Homozygote for Val6 die without treatment, ignore malariamalaria

❖ Cool fact: can treat by turning fetal hemoglobin Cool fact: can treat by turning fetal hemoglobin back onback on

❖ Heterezygotes are OK & resist malariaHeterezygotes are OK & resist malaria

❖ Homozygote of Glu6 healthy, susceptible to malariaHomozygote of Glu6 healthy, susceptible to malaria

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Another way

❖ The product of the ‘duffy’ gene is on the surface of RBCsThe product of the ‘duffy’ gene is on the surface of RBCs

❖ The malaria protozoan attaches hereThe malaria protozoan attaches here

❖ ““Fy(a+b+): 49% Caucasians, 1% African Americans, 9% ChineseFy(a+b+): 49% Caucasians, 1% African Americans, 9% ChineseFy(a-b+): 34% Caucasians, 22% African Americans, <1% ChineseFy(a-b+): 34% Caucasians, 22% African Americans, <1% ChineseFy(a-b+): 17% Caucasians, 9% African Americans, 91%% ChineseFy(a-b+): 17% Caucasians, 9% African Americans, 91%% ChineseFy(a-b-): 0% Caucasian, 68% African Americans*, 0% ChineseFy(a-b-): 0% Caucasian, 68% African Americans*, 0% Chinese

❖ There are trade-offs in susceptibility to other diseases, including There are trade-offs in susceptibility to other diseases, including cancercancer

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Source: http://en.wikipedia.org/wiki/Duffy_antigen_system

* >90% of West African blacks

Cystic Fibrosis & CFTR

❖ Chloride channel—helps sweat and ‘lubricate’ b/c Chloride channel—helps sweat and ‘lubricate’ b/c water follows the Cl- ions outwater follows the Cl- ions out

❖ Great thing in hot weatherGreat thing in hot weather

❖ In the cold, not as essential…In the cold, not as essential…

❖ and can be over-triggered by dysentery diseasesand can be over-triggered by dysentery diseases

❖ appears appears that heterozygotes may be more resistantthat heterozygotes may be more resistant

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FYI: Cycle of fevers & infection

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❖ 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_malaria/