Sickle Cell Anemia

Introduction
• Hereditary disease
• Blood disorder
• Mutation in the Hemoglobin
Beta Gene
• Found on chromosome 11
• Causes abnormally shaped
red blood cells
• A normal red blood cell is
shaped as a round donut
• Sickle cell has a shape like a
sickle or a “ C “ form
 Hemoglobin Gene
 The HBB gene codes for the protein
hemoglobin
 Hemoglobin contains iron and
transports oxygen from the lungs to
the peripheral tissues.
 The HBB protein is 146 amino acids
long.
 The HBB gene is found on
chromosome 11.
 Location of the HBB Gene:
Chromosome 11

Chromosome Map From:

http://www.ncbi.nlm.nih.gov/mapview/maps.cgi?ORG=hum&CHR=11&MAPS=ideogr%5B11pter%3A11qter%5D,loc
%5B0.000000%3A142127415.000000%5D&query=e:HBB
Normal Hemoglobin
 Globin
 Tetramer
 Protein with 4 subunits
 Heme
 One per subunit
 Has an iron atom
 Carries O2
 Found in red blood cells
 It starts with MUTATION

dominant

Negatively
charged

recessive
Hydrophobic

The sickle cell allele results

from a single point mutation
in the gene coding for
hemoglobin
 Change in Protein Structure
HB A1C
HB S

Because valine is hydrophobic, it is

“pushed” to the other HB molecules. This
behavior creates polymers. It happens
mostly when the molecule is carrying little
O2
 Change in Shape
 Polymerization occurs after the
RBCs have released their
oxygen molecules
 When the RBC returns to the
lungs and oxygen is bound, the
HB depolymerizes.
 This back and forth change
causes the RBC membrane to
become rigid
Shape causes problems
Red blood cells Going through Vessels
 Pleotropy
 A singe gene
influences more than
one phenotypic trait.
 Genes that exert
effects on multiple
aspects of physiology
or anatomy are
pleiotropic
 Symptoms of Sickle Cell
o i n t pain
one/ j
n d b
o m inal a
 Abd lessness p u b erty
B r ea th w t h and

e d gr o
l a y v er
 De e a n d f e
d s kin)
g u e
 Fati ce (yellow
 Jau
ndi
P a le ness rate
 h e a r t f ec t i on
id in
 Rap r risk for u l t s can
ate ad gs
 Gre scents and n their le
A d o le
u l c er so
 op
devel ain
C he st p i r st – when s,
 ive t h s
dnes ck of eye
c e ss b l in
 Ex e si ght, o the ba
P o o r e n’t get t constant e to not
y
 ca a opl
blooddon’t haveausing pe * About 30% of Jamaican
they ishment, c patients with Sickle Cell
nour le to see
be ab develop ulcers in comparison
to 1% of Americans
Diseases and Conditions people with
Sickle Cell are likely to develop:
 Acute chest syndrome
 Aplastic crisis
 Dactylitis – swelling of the hands and feet
 Painful crises: really painful episodes when blood cells
are blocked from going to certain parts of the body –
pain can occur anywhere, but it is usually in the chest,
arms, and legs
 Enlarged spleen – sickle cells pool in the spleen, and in
some cases there is no spleen in the body.
 Stroke
 Hematuria
An enlarged
and
unhealthy
spleen from
someone
An x-ray of a hand with Sickle
swollen from dactylitis Cell
Peripheral Blood Smears

Why isn’t the mutant

sickle cell gene
eliminated by natural
selection?
 Prevalence
o It is estimated the up to
80,000 people in America
have Sickle Cell Disease
o 1/500 African Americans
have Sickle Cell Disease
o 1/1000 -4000 Hispanics
have Sickle Cell
o 1/12 African Americans are
carriers for Sickle Cell
o 1/50 Asians are carriers for
Sickle Cell
o 1/100 Greeks are carriers
for Sickle Cell
Sickle cell frequency

 High frequency of heterozygotes

 1 in 5 in Central Africans = HbHs
 This is unusual for allele with severe
detrimental effects in homozygotes
1 in 100 = HsHs
usually die before reproductive age
 QUESTION???

Why is the Hss allele maintained at such high

levels in African populations?
 Patterns of Natural Selection
 Genes provide the source of variation.
 The environment selects for the best adapted
phenotype.
 An allele is only common where it will provide an
advantage. (Natural Selection)
 Mutations can be neutral, harmful or beneficial
1. Harmful mutations result in dysfunctional
proteins, they occur frequently but they are
selected against and remain rare.
2. Beneficial mutations allow the cell to produce a
new or improved protein and gives the individual a
selective advantage. They are rare, but are
selected for and become more common over time.
 QUESTION???

Is there some selective advantage of being

heterozygous… HbbHss
 Sickle cell and malaria

Distribution of the sickle cell allele Distribution of Malaria

As you can see, the areas where

Malaria is present and the Sickle
Cell allele is present are
overlapping.
Plasmodium
Malaria Prognosis
 Malaria is one of the planet's deadliest diseases and
one of the leading causes of sickness and death in
the developing world.
According to the World Health
Organization

 300 to 500 million clinical

cases of malaria each year
 1.5 to 2.7 million deaths.
 Children aged one to four
are the most vulnerable to
infection and death.
According to the World Health
Organization
 Malaria kills more than one
million children - 2,800 per day
- each year in Africa alone.
 In regions of intense
transmission, 40% of toddlers
may die of acute malaria
 Malaria is responsible for as
many as half the deaths of
African children under the age
of five.
 Heterozygote Advantage
Hypothesis:
In malaria-infected  The recessive sickle-cell allele
cells, the O2 level is produces hemoglobin with reduced
lowered enough to capacity to carry oxygen
cause sickling which  This mutation also confers malaria
kills the cell & destroys resistance in heterozygotes
the parasite.
 This heterozygote advantage leads
to a larger proportion of the
recessive allele than usual in areas
where malaria is widespread
 These populations exhibit balanced
polymorphism between the
mutant and wild-type alleles
An Experiment on Sickle Cell and
Malaria in 2005
There were over 1000 people
chosen from Kenya, which is a
place where Malaria is very
prominent
The doctor performing the
study, Dr. Tom Williams, found
that the protection to Malaria
from having the Sickle Cell trait
rose from 20% in the first two
years of life to 50% and over by
the age of 10.
His theory of the resistance of
people with sickle cell trait
results from the immune system
building a defense.
 Heterozygote Advantage
 In tropical Africa, where malaria is common:
 homozygous dominant (normal)
 reduced survival or reproduction from malaria: HbHb
 homozygous recessive
 reduced survival & reproduction from sickle cell anemia: HsHs
 heterozygote carriers
 survival & reproductive advantage: HbHs

Frequency of sickle cell allele & distribution of malaria