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Sickle Cell Genetics and Probability Analysis

The document discusses the genetics of sickle cell disease, detailing the mutation in hemoglobin that causes the condition and its implications for individuals with different genotypes. It includes a lesson plan with procedures for watching a film and answering questions related to Mendelian genetics, probability, and chi-square statistics. Additionally, it features exercises involving pedigrees and the impact of sickle cell trait on malaria resistance in various populations.

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13 views12 pages

Sickle Cell Genetics and Probability Analysis

The document discusses the genetics of sickle cell disease, detailing the mutation in hemoglobin that causes the condition and its implications for individuals with different genotypes. It includes a lesson plan with procedures for watching a film and answering questions related to Mendelian genetics, probability, and chi-square statistics. Additionally, it features exercises involving pedigrees and the impact of sickle cell trait on malaria resistance in various populations.

Uploaded by

brandonbaratian
Copyright
© All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
Available Formats
Download as PDF, TXT or read online on Scribd

The Making of the Fittest: LESSON

Natural Selection in Humans STUDENT HANDOUT

MENDELIAN GENETICS, PROBABILITY, PEDIGREES,


AND CHI-SQUARE STATISTICS
INTRODUCTION

Hemoglobin is a protein found in red blood cells that transports oxygen throughout the body. The hemoglobin protein
consists of four polypeptide chains, two alpha chains and two beta chains. Sickle cell disease (also called sickle cell
anemia) is caused by a genetic mutation in the DNA sequence that codes for the beta chain of the hemoglobin protein.
The mutation causes an amino acid substitution, replacing glutamic acid with valine. Due to this change in amino acid
sequence, the hemoglobin tends to precipitate (or clump together) within the red blood cell after releasing its oxygen.
This clumping causes the red blood cell to assume an abnormal “sickled” shape.

Individuals who are homozygous for the normal hemoglobin allele (HbA) receive a normal hemoglobin allele from each
parent and are designated AA. People who are homozygous for normal hemoglobin do not have any sickled red blood
cells. Individuals who receive one normal hemoglobin allele from one parent and one mutant hemoglobin, or sickle cell
allele (HbS), from the other parent are heterozygous and are said to have the “sickle cell trait.” Their genotype is AS.
Heterozygous individuals produce both normal and mutant hemoglobin proteins. These individuals do not have sickle
cell disease and most of their red blood cells are normal. However, due to having one copy of the sickle cell allele, these
individuals do manifest some sickling of their red blood cells in low-oxygen environments. People with sickle cell disease
are homozygous for the sickle cell allele (SS genotype); they have received one copy of the mutant hemoglobin allele
from each parent. The resulting abnormal, sickle-shaped red blood cells in these people block blood flow in blood vessels,
causing pain, serious infections, and organ damage.

PROCEDURE
1. Watch the film The Making of the Fittest: Natural Selection in Humans. While watching, pay close attention to the
genetics of the sickle cell trait and the connection to malaria infection.
2. Answer the following questions regarding genetics, probability, pedigrees, and the chi-squared statistical analysis
test.

Published July 2012


[Link] Page 1 of 12
The Making of the Fittest: LESSON
Natural Selection in Humans STUDENT HANDOUT

QUESTIONS
MENDELIAN GENETICS AND PROBABILITY
1. If two people who have the sickle cell trait have children, what is the chance that a child will have normal red blood
cells in both high- and low-oxygen environments? What is the chance that a child will have sickle cell disease? Write
the possible genotypes in the Punnett square.

In high- and low-oxygen environments:


Normal Red Blood Cells: ____________

Sickle Cell Disease: ____________

a. What is the chance that a child will carry the HbS gene but not have sickle cell disease? ___________________
b. What are the chances that these parents will have three children who are homozygous for normal red blood
cells? (show work) ___________________________
c. What are the chances that these parents will have three children who have both normal and mutant
hemoglobin beta chains? (show work) ___________________________
d. What are the chances that all three of their children will show the disease phenotype? (show work)
___________________________
e. What are the chances that these parents will have two children with the sickle cell trait and one with sickle cell
disease? (show work) ___________________________
f. In the cross above, if you know that the child does not have sickle cell disease, what is the chance that he/she
has the sickle cell trait? ___________________

2. An individual who has the sickle cell trait has children with an individual who does not have the HbS allele.
a. What are the genotypes of the parents? ____________________
b. Show all possible genotypes of their children in a Punnett square. State the genotype and phenotype ratios of
the offspring.

_____________________________________
_____________________________________
_____________________________________
_____________________________________

c. What are the chances that any one of this couple’s children will have sickle cell disease? __________________
d. If this couple lives in the lowlands of East Africa, what are the chances that one of their children would be
resistant to malaria if exposed to the malaria parasite? _________________

[Link] Page 2 of 12
The Making of the Fittest: LESSON
Natural Selection in Humans STUDENT HANDOUT

3. If a woman with sickle cell disease had children with a man who has the sickle cell trait:
a. What are the genotypes of the parents? ____________________
b. What is the genetic makeup of the gametes the mother can produce? ___________
c. What is the genetic makeup of the gametes the father can produce? ___________
d. Show all possible genotypes of their children in a Punnett square and summarize the genotype and phenotype
ratios of the possible offspring.

_____________________________________
_____________________________________
_____________________________________
_____________________________________

e. What are the chances that any one of this couple’s children will have sickle cell disease?
_______________________________________
f. If this couple moves to the lowlands of east Africa and has children, which of their children would be more likely
to survive? Explain your answer.
_____________________________________________________________________________________________
_____________________________________________________________________________________________
_____________________________________________________________________________________________

4. In humans, blood type is a result of multiple alleles: IA, IB, and iO. A few simple rules of bloodtype genetics are:
IA is dominant over iO. IB is dominant over iO. IAIB are codominant.
Two parents heterozygous for type A blood and who have the sickle cell trait have children. Answer the following
questions:

a. What is the genotype of the parents? ____________________


b. What are the genetic makeup of all the possible gametes they can produce? ____________________
c. Complete the dihybrid Punnett square to determine the frequency of the different phenotypes in the offspring.
Note: Consider blood type and normal vs. mutant hemoglobin in the various phenotypes.

_____________________________
_____________________________
_____________________________
_____________________________
_____________________________

[Link] Page 3 of 12
The Making of the Fittest: LESSON
Natural Selection in Humans STUDENT HANDOUT

5. Now, let’s try a different way of solving a dihybrid cross. Because of Mendel’s (2nd) Law of Independent Assortment,
you can work with the blood-type gene and the hemoglobin gene separately. Set up two monohybrid crosses with
the following parents: Mom is heterozygous for type B blood and has the sickle cell trait, while Dad has type AB
blood and also has the sickle cell trait.

a. What are the chances that a child of this couple will have type B blood and have the sickle cell trait? (show work)
_________________________________________
b. What are the chances that a child will have type AB blood and will not have the sickle cell disease? (show work)
_________________________________________
c. What are the chances that a child will have type B blood and have the sickle cell disease? (show work)
_________________________________________
d. What are the chances that a child will have type B blood and at least some normal hemoglobin? (show work)
_________________________________________

[Link] Page 4 of 12
The Making of the Fittest: LESSON
Natural Selection in Humans STUDENT HANDOUT

PEDIGREES
6. The following pedigree traces sickle cell disease through three generations of a family. Use the pedigree to answer
the following questions.

a. What is the genotype of the father in the first generation? ___________________


b. What is the genotype of the daughter in the second generation? ___________________
c. What is the genotype of individual 3 in the second generation? How do you know?
_____________________________________________________________________________________________
_____________________________________________________________________________________________
_____________________________________________________________________________________________
d. If the couple in the second generation has another child, what are the chances the child will have sickle cell
disease? __________ Have the sickle cell trait? __________ Have completely normal hemoglobin? __________
e. If the entire family moves to the lowlands of East Africa, four of the five males in the pedigree will have two
genetic advantages over the other individuals in the family. Explain the two advantages.
_____________________________________________________________________________________________
_____________________________________________________________________________________________
_____________________________________________________________________________________________
_____________________________________________________________________________________________
_____________________________________________________________________________________________
_____________________________________________________________________________________________

[Link] Page 5 of 12
The Making of the Fittest: LESSON
Natural Selection in Humans STUDENT HANDOUT

7. The following pedigree traces sickle cell disease through four generations of a family living in New York City. Use the
pedigree to answer the following questions.

a. What is the genotype of the mother in the first generation? __________


b. What are the possible genotypes of the father in the first generation? __________
c. What can you say about the genotype of all the children of the couple in the first generation? Explain your
answer.
_____________________________________________________________________________________________
_____________________________________________________________________________________________
_____________________________________________________________________________________________

d. Regarding the answer to part c, based on where the family resides, why would this genotype be considered a
disadvantage? _________________________________________________________________________________
_____________________________________________________________________________________________
e. What are the genotypes of the parents in the third generation?
Mother: _________ Father: _________ Explain how you know.
_____________________________________________________________________________________________
_____________________________________________________________________________________________
f. What is/are the possible genotype(s) of the mother in the second generation? __________
g. If the couple in the third generation has another child, what are the chances the child will have sickle cell
disease? __________
Have the sickle cell trait? __________
Be homozygous for normal red blood cells? __________
Be resistant to malaria and not have sickle cell disease? __________

[Link] Page 6 of 12
The Making of the Fittest: LESSON
Natural Selection in Humans STUDENT HANDOUT

8. The following pedigree traces sickle cell disease through four generations of a family living in the highlands of
eastern Africa. Use the pedigree to answer the following questions.

a. What are the genotypes of the following individuals? (If more than one genotype pertains, include all
possibilities.)
Individual #1: __________ Individual #10: __________
Individual #2: __________ Individual #13: __________
Individual #7: __________ Individual #17: __________
b. If individuals 13 and 14 have another child, what are the chances that he or she will have sickle cell disease?
______________
c. If the same couple has 3 more children, what are the chances that the 3 kids will have the sickle cell trait? (show
work) ___________________________________________
d. Based on where this family lives, is the sickle cell trait genotype a genetic advantage? Explain.
_____________________________________________________________________________________________
_____________________________________________________________________________________________
_____________________________________________________________________________________________
_____________________________________________________________________________________________

e. If individuals 8 and 9 have 4 more children, what are the chances two of them will be homozygous for normal
red blood cells? Explain why.
_____________________________________________________________________________________________
_____________________________________________________________________________________________
_____________________________________________________________________________________________
_____________________________________________________________________________________________

[Link] Page 7 of 12
The Making of the Fittest: LESSON
Natural Selection in Humans STUDENT HANDOUT

9. Imagine that you are a genetic counselor, and a couple planning to start a family comes to you for information.
Jerome was married before, and he and his first wife had a daughter with sickle cell disease. The brother of his
current wife, Michaela, died of complications from sickle cell disease, but neither of her parents has the disease.
a. Draw a pedigree representing this family. Be sure to clearly label Jerome and Michaela.

b. What is the probability that Jerome and Michaela will have a baby with sickle cell disease? (Note that neither
Jerome nor Michaela have sickle cell disease.) Show your work.
_________________________________________________________________________________________________
_________________________________________________________________________________________________
_________________________________________________________________________________________________

10. Natasha and Demarcus are planning on having children. Each has a sister with sickle cell disease. Neither Natasha nor
Demarcus nor any of their parents have the disease, and none of them has been tested to see if they have the sickle
cell trait.
a. Draw a pedigree representing this family. Be sure to clearly label Natasha and Demarcus.

b. Based on this incomplete information, calculate the probability that if this couple has a child, the child will have
sickle cell disease.
_________________________________________________________________________________________________
_________________________________________________________________________________________________
_________________________________________________________________________________________________

[Link] Page 8 of 12
The Making of the Fittest: LESSON
Natural Selection in Humans STUDENT HANDOUT

CHI-SQUARE STATISTICS
11. Multiple couples living in a small village in the eastern African lowlands, all of whom are heterozygous for the HbS
allele, have 500 children among them. Of these children, 139 are homozygous for HbA, 279 are heterozygous for HbS,
and 82 suffer from sickle cell disease. Are these data statistically significant? Explain using a chi-squared statistical
analysis test.

Phenotype/Genotype Observed (o) Expected (e) (o-e) (o-e)2/ e

a. What is the chi-square value (χ2)? __________


b. Calculate the degrees of freedom (df). __________
c. Using the Critical Values Table attached (pg. 12), determine the p value. __________
d. Interpret the p value as it relates to these data. Explain the significance.
_____________________________________________________________________________________________
_____________________________________________________________________________________________
_____________________________________________________________________________________________
_____________________________________________________________________________________________
e. Which of the children have the greatest chance of survival? Explain why.
_____________________________________________________________________________________________
_____________________________________________________________________________________________
_____________________________________________________________________________________________
_____________________________________________________________________________________________
_____________________________________________________________________________________________

[Link] Page 9 of 12
The Making of the Fittest: LESSON
Natural Selection in Humans STUDENT HANDOUT

12. Believe it or not, there are 50 couples all with the same blood type and hemoglobin genotypes. They live on a small,
isolated Pacific island on which very few mosquitoes have been identified. All the individuals are heterozygous for
type A blood and have the sickle cell trait. The fifty couples have had 224 children over the years. The children were
all tested for blood type and for the presence of the sickle cell allele. Here are the results:
Number of
Blood test results
Children
Type A, normal RBCs 48
Type O, normal RBCs 18
Type A, sickle cell trait 92
Type O, sickle cell trait 33
Type A, sickle cell disease 27
Type O, sickle cell disease 6
Are these data significant? Explain using a chi-squared statistical analysis test. (Use the table below if you need
assistance.)
Phenotype Observed (o) Expected (e) (o-e) (o-e)2 /e

a. What is the chi-square value (χ2)? __________


b. Calculate the degrees of freedom (df). __________
c. Using the Critical Values Table attached (pg. 12), determine the p value. __________
d. Interpret the p value as it relates to these data. Explain the significance.
_____________________________________________________________________________________________
_____________________________________________________________________________________________
_____________________________________________________________________________________________
e. From what you know about hemoglobin, sickle cell disease, and blood type, what selection pressure is acting on
this population of children causing the null hypothesis to be rejected? Explain your answer. (Hint: Look at the
actual differences between the observed and expected numbers.)
_____________________________________________________________________________________________
_____________________________________________________________________________________________
_____________________________________________________________________________________________
_____________________________________________________________________________________________

[Link] Page 10 of 12
The Making of the Fittest: LESSON
Natural Selection in Humans STUDENT HANDOUT

f. Due to the increase in global travel and the prevalence of invasive species, the Anopheles mosquito carrying the
malaria parasite was inadvertently introduced to this isolated Pacific island. A researcher, one hundred years
from the present day, decides to complete a follow-up study and monitors another 50 couples, all of whom are
heterozygous for type A blood and have the sickle cell trait. These couples had 136 children. Based on the
introduction of the Anopheles mosquito carrying the malaria parasite, predict scientifically logical observed
numbers of children for each genotype possibility and complete a chi-squared statistical analysis test.
Predicted Observed
Phenotype Expected (e) (o-e) (o-e)2/ e
(o)

i. What is your predicted chi-square value (χ2)? __________


ii. Calculate the degrees of freedom (df). __________
iii. Using the Critical Values Table attached (pg. 12), determine the predicted p value. __________
iv. From your predicted numbers, do you accept or reject the null hypothesis? __________
v. Based on what you know about hemoglobin, sickle cell disease, blood type, and malaria, what selection
pressures are acting on this population of children? Explain your answer.
_____________________________________________________________________________________________
_____________________________________________________________________________________________
_____________________________________________________________________________________________
_____________________________________________________________________________________________
_____________________________________________________________________________________________

[Link] Page 11 of 12
The Making of the Fittest: LESSON
Natural Selection in Humans STUDENT HANDOUT

CRITICAL VALUES TABLE


p
0.995 0.975 0.9 0.5 0.1 0.05 0.025 0.01
df
1 0.000 0.000 0.016 0.455 2.706 3.841 5.024 6.635
2 0.010 0.051 0.211 1.386 4.605 5.991 7.378 9.210
3 0.072 0.216 0.584 2.366 6.251 7.815 9.348 11.345
4 0.207 0.484 1.064 3.357 7.779 9.488 11.143 13.277
5 0.412 0.831 1.610 4.351 9.236 11.070 12.832 15.086
6 0.676 1.237 2.204 5.348 10.645 12.592 14.449 16.812
7 0.989 1.690 2.833 6.346 12.017 14.067 16.013 18.475

AUTHOR:
Ann Brokaw
AP Biology Teacher
Rocky River High School
Rocky River, Ohio

[Link] Page 12 of 12

Common questions

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Understanding Mendelian genetics and probabilities helps in predicting the outcomes of sickle cell disease inheritance by allowing us to calculate the likelihood of different genotypes and phenotypes in offspring based on parental genotypes. Using Mendel's laws of inheritance, such as segregation and independent assortment, and tools like the Punnett square, we can determine the probability of an offspring inheriting the HbS allele from one or both parents, leading to traits like being a carrier or having the disease .

If a person with the sickle cell trait (AS) has children with a person without the HbS allele (AA), the possible genotypes of their children are AA and AS. The corresponding phenotypes are normal hemoglobin (AA) and sickle cell trait (AS). There is no possibility of the child having sickle cell disease since neither parent has two HbS alleles .

Sickle cell disease is considered a genetic disadvantage in non-malarial regions like New York City because the protection against malaria offered by the sickle cell trait is irrelevant in these environments. Instead, individuals homozygous for the HbS allele suffer from the severe health complications associated with sickle cell disease (e.g., pain, organ damage), which outweigh any potential benefits. Thus, in the absence of malaria, there is no selective advantage of possessing the HbS allele, and it primarily represents a health burden .

To calculate genotype probabilities for offspring when both parents have type A blood and the sickle cell trait, you need to perform a dihybrid cross considering both the ABO blood type alleles (IA, i) and the hemoglobin alleles (HbA, HbS). Since both parents are heterozygous for both traits (IAi, AS), the Punnett square will have 16 squares representing combinations of these alleles. The probabilities for each genotype combination (e.g., IAIAAS) are determined by counting the frequency of each combination in the Punnett square relative to the total possibilities .

The chi-square test results indicate whether the observed distribution of genotypes (139 AA, 279 AS, 82 SS) among the children is statistically significant based on the expected Mendelian ratios (1:2:1). The calculated chi-square value, degrees of freedom, and corresponding p-value help determine if the deviations in frequency from the expected ratios are due to chance or other biological factors. If the p-value is low, it suggests that factors such as selection pressures (e.g., malaria resistance) may be influencing genotype frequencies .

The probability that two parents with the sickle cell trait (both with genotype AS) will have a child with sickle cell disease is 25%. This is because there is a 1 in 4 chance (AA, AS, SA, SS) that the child will inherit the sickle cell allele from both parents, resulting in the SS genotype, which corresponds to sickle cell disease .

Examining a pedigree allows us to trace the inheritance pattern of sickle cell disease across generations. By identifying individuals with various genotypes and phenotypes, one can determine patterns of dominant and recessive allele transmission. For instance, if the disease is present only in individuals homozygous for the HbS allele, the disease follows an autosomal recessive inheritance pattern. Pedigrees can also help identify potential carriers (heterozygous individuals) among family members, which aids in predicting risks for future offspring .

The chi-square test in genetic data analysis helps determine if observed genetic distributions align with expected outcomes under a given hypothesis, such as Mendelian inheritance. In the context of sickle cell alleles, this test can reveal if deviations from expected frequencies in a population are due to random chance or external factors such as natural selection pressures. A significant chi-square result could indicate selection for or against certain genotypes, providing insight into evolutionary dynamics within the population .

Individuals with the sickle cell trait (HbAS) have reproductive advantages in the lowlands of East Africa because the heterozygous condition offers protection against malaria, a prevalent disease in the region. This protection increases the likelihood of survival and subsequent reproduction, thereby passing on the advantageous heterozygous genotype to future generations and maintaining the HbS allele in the population despite its potential deleterious effects when homozygous .

The sickle cell trait provides an evolutionary advantage in regions with high malaria prevalence because individuals who are heterozygous for the sickle cell allele (HbAS) have some resistance to malaria. The presence of the mutant hemoglobin S in these individuals disrupts the life cycle of the malaria parasite within red blood cells, providing a survival advantage over those with only normal hemoglobin (HbAA), who are fully susceptible to malaria. This selective pressure maintains the allele in the population despite its deleterious effects when homozygous .

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