Activity: The Sickle Cell Gene (for better or for worse)
Text in blue are answers for Instructors.
Sickle cell anemia is a human disease characterized by the presence of a different form of
hemoglogin the major protein in the red blood cells. This protein is crucial in enabling
gas transfer O2 and CO2 between organs and the bloodstream. In case of low oxygen, the
blood cells of people with the less frequent form won’t have retain the shape and
flexibility of regular red bloodcells. They will take the shape of sickle (thus the name)
and lose most of their deformability with the potential risk of clogging fine blood vessels.
This will lead to severe manifestations at the organism and will threaten the life of the
individual.
Figure 1: picture of normal and sickled red blood cells and schematic of a clogging event
due to the presence of sickled red blood cells.
Q1: Sickle cell anemia is the first disease which molecular origin has been proven by
Linus Pauling in 1949. It turned out that it was a point mutation in the sequence of the
hemoglobin gene on the chromosome 11. What is a point mutation? How many alleles of
that gene do you think there is/are?
A point mutation is a mutation in only one base in the DNA sequence of a gene. This
gene will then have two alleles, the allele with the not mutated sequence and another
allele with the mutated sequence.
Q2: The allele that is most frequent in the population has the following sequence and is
called HbA allele:
CTG ACT CCT GAG GAG AAG TCT.
The mutant sequence (Hb S) is:
CTG ACT CCT GTG GAG AAG TCT.
What is the difference in terms of nucleotide? Using the genetic code (pg. 681 in
“Integrated Science” textbook) transform that sequence in amino acids. What difference
is there in between the two proteins?
Above schematic provides the answer. Point mutations from A to T, which results in
change of a single amino acid from “Glu” to “Val”.
Q3: If we have a couple that are both heterozygote for this genes, what is the probability
for them to have heterozygote offspring? AA offsprings? SS offspring?
Above schematics provides the answers: 50% heterozygous, 25 % AA and 25 % SS.
Q4: While individuals with one copy of the HbS gene and one copy of the HbA version
experience pain and some debility, individuals with two copies of the HbS form are very
severely affected: they have a shorter life expectancy and many die in childhood.
Suppose that HbS represents a relatively new mutation in a particular population and that
many people carry this mutation. If we follow the prevalence of the mutation in the
population would you expect it to decrease or increase over time? Why?
If the mutation has such a deleterious effect when present in two copies, individuals
carrying both copies are not likely to reproduce (as they might die before being able
to carry or father children) then the frequency of the mutation should decrease
substantially due to (negative) natural selection – assuming that is, that
heterozygotes with one HbA and one HbS do not have a selection advantage.
Whether or not the gene persists at all under this assumption depends on how badly
individuals with one copy are affected. If the debility is mild, one would still expect
the frequency of the gene to decrease over time. The only way the gene could persist
with any reasonable frequency would be if it actually conferred an advantage
(positive selection).
Below are two maps: one illustrates the frequency of the HbS form of the gene and the
other displays the incidence of endemic malaria.
Q5: How does the geographic incidence of malaria (the infectious environment of our
species) compare to the geographic prevalence of the HbS form of the hemoglobin gene?
The highest incidence of the HbS form of the gene occurs in areas (in Africa and
India) where malaria is endemic, though there are regions with malaria where
people do not carry HbS.
Q6: What does this comparison suggest about the ability of what seems like a
deleterious mutation (HbS) to persist in human populations? How could you test this
suggestion? Relate these ideas to assertion that "a gene's full meaning can never be
known in advance”: what are two different “meanings” of HbS and what determines
which is most applicable at a particular place and time?
The comparison raises the possibility that malaria and HbS are somehow
associated. One way they could be associated would be if malaria were an agent of
natural selection. For example, perhaps people with HbS and red blood cells that
can sickle are resistant to the effects of malaria, even if they have only one copy of
the gene. You could test this idea by comparing the incidence of infection in carriers
versus non-carriers (a correlational approach). You could also create a mouse model
of the disease by gene transfer and see whether mice with the HbS form of the gene
are more difficult to infect with malaria than those with the HbA form (the
assumption underlying the use of such a model approach is that mouse hemoglobin
works the same way as human hemoglobin). This latter approach is experimental.
The two meanings of HbS are: (1) a survival disadvantage related to impeded blood
flow and transport of oxygen versus (2) a putative survival advantage in the
presence of endemic malaria. The environment (selective pressure) determines
which is more relevant for a given individual at a given time, if that individual
carries one copy of HbA and one copy of HbS. For individuals with two copies of
HbS, meaning (1) predominates.