HANDOUT 21: Sickle Cell and Selection
In 1910, James B. Herrick discovered sickle-shaped red blood cells
(RBC’s) in the blood of one of his patients. A short while after Herrick had
written an account of this discovery, other doctors observed these same
sickle-shaped cells. Today we know the sickle-shaped RBC’s are due to a
hemoglobin molecule that differs from the “normal” hemoglobin protein by
one amino acid. This trait is determined genetically.
The presence of the Sickle-cell trait is diagnosed when a patient’s
blood sample is placed in a chamber with very little oxygen. Red blood cells
shape changes and the sickle-shaped deformity then occurs. If the blood of
the patient’s parents is examined the same way, similar deformities maybe
found in the RBC’s of one or both parents. The parents usually have no
permanent anemia. However, some sickling of their RBC’s may occur if they
go to high elevations or engage in prolonged physical exertion. This mild
sickling without permanent anemia is called sickle-cell trait. Having sickle
shaped cells all the time is called Sickle-cell Disease.
Look at the pedigree below.
1
6
7
8
2
3
4
5
9
10
11
12
KEY:
= Male
= Normal RBC
= Female
= Sickle–cell Trait
13
14
15
16
17
= Sickle-cell Anemia
1. What are the different phenotypes in this family?
2. If only one gene (with 2 alleles) is involved in this trait. How many genotypes might you expect? Using the
letter “H” to represent the allele for normal hemoglobin and “h” for the sickle-cell allele, what are the
genotypes?
3. In the pedigree, what is the genotype of the P1 individuals?
4. Notice individual #3 has very severe sickling. Many people with severe sickling die in infancy or early
childhood. What genotype would you expect this individual to have?
5. Individuals 1 & 2, 6 through 11, and 13 through 15 all have the same genotype. What is it?
6. If individual #16 marries a person with the same genotype, what is the probability of their children having
sickle-cell anemia? Having sickle-cell trait? Normal RBC’s? Show this cross.
7. What kind of monohybrid inheritance is at work here?
In some populations of black Africans, the sickle-cell trait may be found in as many as 40% of the individuals. The gene is not
found in most Caucasian populations. If 4/10 of the adult population is heterozygous for this trait, the chance of two
heterozygotes mating is 4/10 x 4/10 = 16/100. This 16% or about 1/6 of matings would involve two heterozygotes.
8. What fraction of all the children born in such a population would be homozygous for sickle cell anemia?
9. Would you expect individuals with sickle-cell trait (Hh) to leave more or fewer surviving descendants than
individuals with normal RBC’s (HH)?
10. How would your answer to #8 affect the frequency of the gene for sickle-cell in the population?
Contrary to what you may assume in your answer to question #8, there is no evidence that the frequency for the sickle cell gene
in these populations is being reduced. The obvious question is then, how can a gene that has these negative effects be
maintained in at such a high level (4/10 of the population) while being selected against so strongly? Scientists have considered
at least three hypotheses to account for the high frequency of sickle cell hemoglobin in Africa. Hypothesis One: involves the
mutation rate of this gene. Hypothesis Two: pertains to differences in fertility between people with the trait and those
without. Hypothesis Three: relates to susceptibility to other diseases.
Hypothesis One: It has been estimated that the normal hemoglobin gene would have to spontaneously mutate into the sickle
cell gene at about 100x a rate of any other human gene to replace the genes lost by selection. There is no evidence for such a
high mutation rate in any human gene.
11. Does this information weaken or strengthen the possibility of this hypothesis explaining the high
frequency of the sickle-cell gene? Why?
Hypothesis Two: There is no evidence that individuals with sickle-cell trait produce more children than non-sicklers.
12.
Is the second hypothesis strengthened or weakened by this information? Why?
Hypothesis Three: This is more difficult to test. The incidence of the trait has been plotted on maps. The gene is most common
in a belt that extends across the central portion of Africa. Malaria is very common in this region. One investigator examined
the blood of 290 children in an East African population. Both malaria and sickle-cell traits were common in the area. The results
are shown below:
Children with Sickle-cell trait
Children with normal RBC’s
13.
Children with Malaria
12 (27.9%)
113 (45.7%)
Children without Malaria
31 (72.1%)
134 (54.3%)
Does this data support or refute the third hypothesis? Why?
Total
43 (100%)
247 (100%)
To further test this hypothesis, 30 volunteers were inoculated with malaria parasites. The volunteers were adult males of about
the same age and physical condition. None of the 30 had malaria parasites at the before the experiment. Of the 30, 15 had
sickle-cell trait and 15 had normal RBC’s. Two of the volunteers with sickle-cell trait and 14 of the normal RBC volunteers
developed malaria. When the observations were completed, the individuals who developed malaria were successfully treated
to stop the disease.
14. How is it that the heterozygote has a selective advantage over both homozygotes in this case?
15. How can a gene that is harmful in some conditions be beneficial in some other conditions?
The incidence of sickle-cell trait in the African American population in the United States between 1790 and 1890 is estimated to
have been about 22% of the population. Today the African American population has an incidence rate of approximately 8% for
sickle-cell trait in our country. Malaria has been almost totally eradicated in the United States.
16. What survival value does the sickle-cell trait have in the conditions of America today?
17. Is the frequency of the sickle-cell gene changing in America? What is the trend and why is it happening?
18. Which of the Hardy-Weinberg conditions is not being met to cause this gene frequency change?
19. Is change this evolution?