Sickle Cell Disease: Genetics and Pedigrees

Hemoglobin is a protein found in red blood cells (RBCs), which transports oxygen throughout the body. The hemoglobin protein consists of four polypeptide subunits: two alpha subunits and two beta subunits. All humans have 2 copies the gene for the alpha chain (gene HBA) and 2 copies of the gene for the beta chain (gene HBB). Some versions (alleles) of the HBB gene result in sickle cell disease (SCD). Sickle cell anemia is the most common SCD.

SCD is caused by a genetic mutation in the DNA sequence that codes for the beta chain of the hemoglobin protein. In sickle cell anemia, the mutation causes an amino acid substitution, adding a valine amino acid to the beta chain instead of a glutamic acid amino acid.

Due to this change in amino acid sequence, the hemoglobin tends to clump together within the RBC after releasing its oxygen. This clumping causes the RBC to assume an abnormal “sickled” shape. The resulting abnormal, sickle-shaped RBCs block blood flow in blood vessels, causing pain, serious infections, and organ damage.

  • People who are homozygous for the normal HBB gene received one normal allele from each parent. All their hemoglobin is normal and called hemoglobin A or HbA. Their genotype is called AA. People with the AA genotype do not have any sickled RBCs.
  • People who are homozygous for the mutant HBB gene received one mutant allele from each parent. All their hemoglobin is abnormal and called hemoglobin S or HbS. Their genotype is called SS. People with the SS genotype have all sickled RBCs environments and haves sickle cell disease (SCD).
  • People who are heterozygous for the HBB gene received a normal allele from one parent and a mutant allele from the other parent. Half of their hemoglobin is HbA and half is HbS. Their genotype is called AS. Most RBCs in AS people are normal, but there is some sickling when oxygen gets low. They are said to have sickle cell trait (SCT). Usually, they do not have any symptoms of SCD.

Interestingly, sickled RBCs can’t get infected very easily with parasites like the protist Plasmodium, which causes the disease malaria. Therefore, people with sickled RBCs are protected against malaria infection.

Plasmodium is transmitted by the Anopheles mosquito. These mosquitos only live in certain regions of the world as shown by the colored regions on the map below. Therefore, people who live in those regions have high malaria transmission rates. This selects for people with sickled RBCs since they don’t die from malaria. Over time, the populations underwent natural selection and ended up having more people in them with the HbS allele. Thus, the frequency of people with SCD and SCT are higher in people who live in places with malaria or if your ancestors lived in a place with malaria.

The colored regions in the map below are places with the Anopheles mosquito, which can carry the malaria parasite, Plasmodium.

Rates of malaria. Blue = no malaria. Yellow = some malaria. Orange = high malaria

 For all multiple-choice questions, underline your answer(s). There is only one correct answer unless the question tells you to pick more than one.

 Using the maps above:

  1. Which location has the highest malaria transmission?
    1. North America
    2. Middle South America
    3. Australia
    4. Northern Africa
    5. Middle Africa
    6. Southern region of East Asia (India, China, Thailand, etc.)
  2. Some mosquito species prefer to bite people instead of other animals. Look at the Anopheles species map. Thinking about your answer to question 1, which species of Anopheles mosquito most likely prefers to bite humans and transmit Plasmodium which causes malaria? Underline your answer choice.
    1. Anopheles messeae
    2. Anopheles darlingi
    3. Anopheles atroparvus
    4. Anopheles gambiae
  1. Two people with SCT have children. Write the possible genotypes of their offspring in the Punnett square. Remember, parent gametes go on the outside and potential offspring from that cross go on the inside. Each offspring should have two alleles.
    1. Mother’s genotype
      1. AA
      2. AS
  • SS
  1. Father’s genotype
    1. AA
    2. AS
  • SS
  1. Cross the parents. Show your work in the fillable Punnett square below.

 

     
     
     
  1. Using your Punnett square above, what is the chance that a child will have normal RBCs in high and low oxygen environments?
    1. No chance
    2. 1/4
    3. 1/2
    4. 3/4
    5. 100% chance
  2. Using your Punnett square above, what is the chance the child will have SCD?
    1. No chance
    2. 1/4
    3. 1/2
    4. 3/4
    5. 100% chance
  3. Using your Punnett square above, what is the chance the child will carry the HbS allele but not have SCD?
    1. No chance
    2. 1/4
    3. 1/2
    4. 3/4
    5. 100% chance

When there’s more than one condition that needs to be true (e.g. 3 children with a certain genotype), multiple each probability together to get to overall probability for all of those events to happen.

  1. Using your answers above and multiplication, what are the chances all three of their children will show the disease phenotype?
    1. No chance
    2. 1/4
    3. 1/16
    4. 1/8
    5. 27/64
    6. 1/64
    7. 100% chance
  2. Using your answers above and multiplication, what are the chances these parents will have two children with SCT and one with SCD?
    1. No chance
    2. 1/4
    3. 1/16
    4. 1/8
    5. 27/64
    6. 1/64
    7. 100% chance
  1. A woman who has SCT has children with a man who doesn’t have the HbS
    1. Mother’s genotype
      1. AA
      2. AS
      3. SS
    2. What is genetic makeup of the gametes the mother can produce? (Recall: Gametes only have 1 allele for each gene in them because they’ll combine with another gamete to make a baby with 2 alleles.)
      1. A and S
      2. A only
      3. S only
    3. Father’s genotype:
      1. AA
      2. AS
      3. SS
    4. What is the genetic makeup of the gametes the father can produce?
      1. A and S
      2. A only
      3. S only
    5. In the below Punnett square, show all the possible genotypes of the kids. Recall: A homozygote (2 copies of the same allele) only makes 1 type of gamete; so, you only need to put that in the Punnett square one time (e.g. SS can only make S gametes.) That’s why there are only 2 boxes.
     
     
  1. What is the genotypic ratio of the offspring?
    1. 1 AA : 2 AS : 1 SS
    2. 1 AA : 1 SS
    3. 1 AS : 1 SS
    4. 3 AA : 1 AS
    5. 1 AA : 1 AS

 

  1. What’s the probability they will have a child who is resistant to malaria but doesn’t have SCD symptoms?
    1. No chance
    2. 1/4
    3. 1/2
    4. 3/4
    5. 100% chance

———

In humans, ABO blood type is a result of three alleles: IA, IB, and i

  • IA results in A-type carbohydrates on your RBCs (red blood cells)
  • IB results in B-type carbohydrates on your RBCs
  • i results in neither A nor B carbohydrates on your RBCs
  • You only need one copy of the allele to get the carbohydrates on your RBCs.
  • There are 4 phenotypes you can have for ABO blood type: Type A, Type B, Type AB, and Type O (this is the letter O – not the number zero)

 

  1. Describe the relationship of the alleles by filling in the table below. An example is given for you.

Answer choices: completely dominant, completely recessive, incompletely dominant, codominant. Answers can be used once, more than once, or not at all.

IA is completely dominant to i
IB is   to i
i is   to IA and IB
IA is   to IB
  1. Here are the 6 genotypes possible. Which of the 4 blood types do they result in?
Genotype Phenotype (blood type)
IA IA  
IAi
IB IB  
IBi
IA IB  
ii  
  1. A woman with heterozygous type B blood (IBi) and a man with heterozygous type A blood (IAi) are having a child. What is the chance that the child has type A blood? Show your work in the Punnett square. Use the correct notation for the alleles with the I/i. You don’t have to use superscripts if you don’t want to.
     
     
     

Using your pedigree above, what’s the probability of a baby with type A blood?

  1. No chance
  1. 1/4
  2. 1/2
  3. 3/4
  4. 100% chance

 

  1. A woman with type O blood and a man with type AB blood are having a child. What are the possible blood types their baby can have? Show your work in the Punnett square.
     
     

Select all possible blood types

  1. Type A
  2. Type B
  3. Type AB
  4. Type O

 

This is a pedigree that traces sickle cell disease through three generations oof a family. Use the pedigree to answer the following questions.

  1. What is the genotype of the daughter in the second generation?
    1. AA
    2. AS
    3. SS
  2. What is the genotype of the father in the first generation? (Hint: Use the genotype of the daughter in the second generation (the question above) to determine this genotype.)
    1. AA
    2. AS
    3. SS
  3. Explain how you figured out this (father in the first generation) genotype:
  1. If the entire family moves to the lowlands of East Africa (wet areas with the Anopheles mosquito carrying Plasmodium), four of the five males in the pedigree will have two genetic advantages over the other individuals in the family. What are they?
    1. Advantage one:
    2. Advantage two:

Imagine that you are a genetic counselor and a couple planning to start a family comes to you for information. Jerome and his first wife have a daughter with SCD. The brother of his current wife, Michaela, died of complications from SCD. Neither of Michaela’s parents have SCD.

  1. Which pedigree below is correct? People with sickle cell disease are shaded in. People without sickle cell disease are empty. People will sickle cell trait are also empty (no half-shading in this pedigree).
    1. Pedigree A
    2. Pedigree B
    3. Pedigree C
    4. Pedigree D
A B
C D
  1. Michaela gets tested and finds out she inherited one sickle cell allele from her dad (she has SCT). What’s the probability that she and Jerome will have a child with SCD?

Hint: Determine Jerome’s genotype first. Then make a Punnett square with Jerome and Michaela.

  1. No chance
  2. 1/4
  3. 1/2
  4. 2/3
  5. 3/4
  6. 100% chance