Transcript Malaria Sickle alleles

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One change.
Multiple origins.
How can you deduce such a thing?
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Pop quiz
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What is the leading cause of death of humankind, summed
over everything, ever?
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How you die
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• 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.
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• Cerebral malaria can cause coma, life-long-learning
disabilities, and death.
http://www.malarianomore.org/pages/what-ismalaria
off topic? Malaria (mala aria = ‘bad air’)
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Plasmodium falciparum
Apparently, we got it from
chimps*
Note the
mosquito!
Image Source: http://www.sanger.ac.uk/PostGenomics/plasmodium/presentations/plasmodium_lifecycle.shtml
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Where malaria does its killing
http://www.worldmapper.org/images/largepng/389.
png
Hypotheses...
Malaria
Sickle alleles
Correlation is obvious. Why might the incidence
of sickle alleles track incidence of malaria?
Source:
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a Fly in the Ointment
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Nucleotide: A => T
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Amino acid: Glu => Val
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Hemoglobin: free => sticky
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Person: healthy =>
anemic
Image: Fig 7.3, Genetics: analysis of genes and genomes (D. Hartl and E. W. Jones)
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Questions/review
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How many ways are there to fail in the making of brown stuff in
the eye? [be blue eyed]
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How many ways are there to fail to turn off your lactase (milksugar digesting) gene after toddlerhood? [be lactose tolerant]
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How many ways are there to have a glutamic acid @ codon 6
of beta-hemoglobin? [let’s consider single nte. changes only]
Not an ideal solution, but a
common one
How could we deduce independent origins?
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Another view of linkage
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What do you observe happening over successive meioses?
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What do you observe not happening?
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What are the consequences for regions of DNA adjacent to
the black circle?
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Conclusion: it’s not nucleotides, but regions of DNA that are
little boats traveling down the generations.
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A small boat (short sequence) is only very rarely re-built
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Inferences
*
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What’s in a distance
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“centimorgan”: span of nucleotides with likelihood of a
recombination event occurring once per 100 generations
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In humans, it’s ca. 1,000,000 nucleotides
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In other words, point A and point B can be MILLIONS of
nucleotides away and not get separated for many generations in
humans
Today’s ref
“A novel sickle cell mutation of yet another origin in
Africa: the Cameroon type
C. Lapoumeroulie et al. Human Genetics 89: 333-7
(1992)
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Changes
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“A plague upon both
your houses”
—spoken by Mercutio, Romeo and Juliet, in response
to… being killed
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Sickle cell anemia
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Homozygote for Val6 die without treatment, ignore malaria
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Cool fact: can treat by turning fetal hemoglobin back on
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Heterezygotes are OK & resist malaria
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Homozygote of Glu6 healthy, susceptible to malaria
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Another way
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The product of the ‘duffy’ gene is on the surface of RBCs
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The malaria protozoan attaches here
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“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
* >90% of West African
blacks
Source:
http://en.wikipedia.org/wiki/Duffy_antigen_system
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Cystic Fibrosis & CFTR
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Chloride channel—helps sweat and ‘lubricate’ b/c water
follows the Cl- ions out
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Great thing in hot weather
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In the cold, not as essential…
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and can be over-triggered by dysentery diseases
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appears that 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_malari