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Natural Selection: Uncovering
Evolutionary Correlations between
Sickle Cell Anemia (HBB gene & HbS
allele), Malaria, and ENT proteins
By: Kali Nason, Kelly Colthorpe, and
Greg Kinstler
Evolutionary Questions about Malaria
and sickle cell anemia?
• What do you think?
Questions??
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What is it sickle-cell anemia?
When did it arise?
How did it evolve?
Why did it evolve?
Where is it most prevalent?
Correlation between endemicity and HbS trait
What are the areas where malaria is most prevalent?
Are there other correlations with this mutation other
than malaria resistance with equal positive effect?
• Is this why the mutation has such a high rate in
endemic areas?
Sickle-cell Anemia
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Autosomal recessive
Normal HbA/HbA
Heterozygote/Carrier of trait HbS/HbA
Homozygous recessive/Sickled HbS/HbS
J. B. S. Haldane (1949)
• Observed many tropical regions where malaria
was endemic and red blood cell disorders such as
sickle-cell anemia and various thalassemias
(**also autosomal recessive either partial or no
synthesis of one of the globin chains in
hemoglobin due to deletion or mutation)
• The “Malaria Hypothesis”: Disorders had become
common in these certain areas because natural
selection increased the prevalence of these traits
to protect individuals from malaria
Geographical Distribution of Malaria
(2005)
A. C. Allison (1954)
• Confirmed “Malaria Hypothesis”
• The geographical distribution of sickle-cell mutation in
the beta hemoglobin gene (HBB) was limited to Africa
and correlated with malaria endemicity (**So there
was clearly some sort of selective advantage for
having the sickle cell trait, otherwise this deleterious
allele would have been selected against)
• Individuals with the HbS trait were resistant to malaria
(**autosomal recessive full blown sickle-cell anemia,
one allele of HbS and one regular…almost no
symptoms at all but resistance still there)
***Point mutation at
position 6 and on the short
arm of the chromosome at
position 11p15.5
Convergent Evolution and Malaria
• Four identified different sickle-cell variants (of
HbS allele) among different African populations
• Suggesting same mutation arose independently
among the different populations several different
times
• ***Beyond HbS, there’s other mutations in the
HBB gene have generated HbC and HbE alleles,
which arose and spread in Africa and in
Southeast Asia
Interesting Correlations
• Haldane was on the right track!
• Different RBC diseases (a-thalassemia, G6PD deficiency, and
ovalocytosis)
• ALL correlate to malaria endemicity and are linked to malaria
resistance
• Mutation in Duffy antigen gene (FY) (**Plasmodium vivax uses this
protein to enter RBCs and mutation in this protein disrupts its
pathway of entry = PROTECTION! Occurs at 100% prevalence in
thru most of sub-Saharan Africa..non existent outside Africa)
• (**Again)Convergent evolution in Southeast Asia (**independent
mutation has arisen of the FY gene)
• ENT proteins possible target for new malaria drug (**get to that in
a bit)
Malaria and the World Health
Organization
• According to WHO “In 2008, there were 247
million cases of malaria and nearly one million
deaths – mostly among children living in
Africa. In Africa a child dies every 45 seconds
of Malaria, the disease accounts for 20% of all
childhood deaths.”
Evolution
• What does this have to do with Evolution?
• EVERYTHING!
• Malaria is one of the most understood
examples of an infectious disease and its
evolutionary drive in humans
EVOLUTIONARY ARMS RACE!
• Malaria is currently treated with a cocktail of drugs
• The initial drug is usually an artemisinin (this wipes out malaria
symptoms)
• Partial treatment…some parasites still present, continue life cycle!
• ACT used in combination = DEATH!
**problem with about partial treatment…without the second
drug many of the patients are not taking it so the life cycle
continues and the parasites become more and more resistant to
the currently known drugs
• Example: Chloroquine and Sulfacoxine-pyrimethamine (SP) **in
the past malaria became resistant to these two drugs. Dire effects
on populations if there are no new drugs in the
making…populations could be wiped out.
• P. falciparum is resistant to most drugs
available and is the deadliest form of any
Plasmodium species (P. vivax, P. knowlesi, P.
ovale)
• Fever Table (**this is why p.falciparum is so
deadly…longer period of time with fever)
Novel Treatments Available??
• No… Unfortunately there are no current new
drugs in development
• Possible ideas!
• ENT proteins (Equilibrative Nucleoside
Transporter proteins)
• **we need to get a one up of the parasite to
create a new drug before it becomes resistant
to the current ones available
ENT proteins?? New target
• Needed by Plasmodium falciparum
• Needs purines (adenosine) for DNA replication
• Steals purines from host
RBCs
ENT proteins are the
pathway which
P. falciparum enters a RBC
ENT’s
• P. falciparum uses the already existing ENT
proteins to channel the needed purines into
the RBC where the parasite is
• Idea behind this is to target these ENT
proteins and inhibit them
• ENTs are highly conserved! Almost no
evolution of this protein through different
organisms
Other ENT proteins
• When P. falciparum’s sequence was entered into
the database the first couple of hits are different
species
• Important why?
• Evolution?
Future
• Pathway inhibited = new drugs = Malaria
wiped out!
• Would sickle cell anemia trait still be
prevalent? Or would evolution select against
it?
• Duffy antigen mutation?
• Lots of evolutionary questions!
References
• http://www.pbs.org/wgbh/evolution/library/01/2/l_012_02.html
• http://findarticles.com/p/articles/mi_6958/is_8_69/ai_n28470765/
pg_4/
• http://www.nature.com/scitable/topicpage/natural-selectionuncovering-mechanisms-of-evolutionary-adaptation-34539
• http://www.ornl.gov/sci/techresources/Human_Genome/posters/c
hromosome/hbb.shtml
• http://www.who.int/mediacentre/factsheets/fs094/en/index.html
• http://en.wikipedia.org/wiki/Thalassemia
• http://blast.ncbi.nlm.nih.gov/Blast.cgi
• http://www.americasurf.info/index.php?qq=uggc%3A%2F%2Fra.jvx
vcrqvn.bet%2Fjvxv%2FZnynevn%2523Flzcgbzf
• http://onlinelibrary.wiley.com/doi/10.1002/ajpa.1330810204/pdf
• http://www.jstor.org/stable/68141