Exam Question on a BASE SUBSTITUTION Mutation.

"Explain the consequence of a base substitution mutation in relation to the process of transcription and translation, using the example of sickle cell anaemia."                                   (8 marks)

The answer to this question needs explaining in four parts, (and you need two points for each)

  1. What is a "base substitution mutation"
  2. How does it affect transcription
  3. How does it affect translation
  4. Specific details of sickle cell anaemia

Read this explanation,  HIGHLIGHT two key points for each section.  Then WRITE you essay answer, without looking at the notes.

  1. What is a base substitution mutation? 
                   -  A mutation is a change in the  genetic code carried on DNA.  
                   -  A base substitution is when the base in the DNA molecule is replaced with another base.

  1. How does this affect Translation?

    The obvious fact is that the mRNA made from this mutated DNA will also have a change in the base sequence.  The RNA made from the second strand of DNA by translation will be:
     
              G A C      U G A      __  __  __     __  __  __    __  __  __    U U C     A G A

    (complete the three missing codons yourself.  Be sure to use the sickle cell gene)

  2. How does it affect translation ?
     
    If you understand translation this is also quite easy too.  The amino acids sequence coded for by the mRNA will have a mistake in it, because the mRNA has a change in one of its bases.
     
    Here you can see that the amino acid in position 6 of the Haemoglobin has changed from Glucine (Glu)  to Valine (Val).  
    When the mRNA is translated (on the ribosome) the chain of amino acids produced is different from the normal gene.

  3. Specific details of sickle cell anaemia



    The mutation of the DNA which causes sickle cell anaemia is just a single base substitution.  This causes one amino acid to change in the polypeptide making part of the protein called Haemoglobin.

    What effect does this have?



    Haemoglobin is found in red blood cells and carries oxygen around the body.
    In sickle cell anaemia the haemoglobin is almost identical (just one amino acid changed) but the red blood cells change shape.
          
    When the red blood cells are de-oxygenated they become sickle shaped.
    This causes blockages in blood vessels.

    The blockages cause other symptoms depending on where the blood vessels get blocked.

  • When the small blood vessels in the hands or feet are blocked, pain and swelling can result.
  • Fatigue, paleness, and shortness of breath — all symptoms of anemia, or a shortage of red blood cells.
  • Pain that occurs unpredictably in any body organ or joint, wherever the sickled blood cells block oxygen flow to the tissues. The frequency and amount of pain varies. Some patients have painful episodes (also called crises) less than once a year, and some have as many as 15 or even more episodes in a year. Sometimes the pain lasts only a few hours; sometimes it lasts several weeks. For especially severe, ongoing pain, the patient may have to be hospitalized and treated with painkillers and intravenous fluids. Pain is the principal symptom of sickle cell anemia in both children and adults.
  • Eye problems. When the retina, at the back of the eye, does not get enough oxygen from circulating red blood cells, it can deteriorate. Damage to the retina can be serious enough to cause blindness.
  • Stroke. The defective hemoglobin damages the walls of the red blood cells, causing them to stick to blood vessel walls. This can result in the development of narrowed, or blocked, small blood vessels in the brain, causing a serious, life-threatening stroke. This type of stroke occurs primarily in children.


  • Inheritance of Sickle Cell anaemia is an example of  MONOHYBRID AUTOSOMAL inheritance.
    It is a single gene on chromosome 11, it affects men and women equally.
    You have to inherit two RECESSIVE alleles to suffer from Sickle Cell Disease.  
    Carriers with one recessive allese are said to have "Sickle Trait"

                                                  

 

Here is the IB markscheme for the question above.

A mutation is a change in DNA sequence;
It changes the mRNA during transcription;
Changed mRNA changes the amino acid sequence;
Sickle Cell condition is caused by a substitution mutation / changes to one codon;
glutamic acid is changed to valine / GAG to GTG;
This mutation changes the shape of haemoglobin /
The haemoglobin becomes less soluble and crystallizes out;
The haemoglobin cannot carry oxygen as well;
The red blood cells sickle / this sickling impairs blood flow;
Sickle cell anaemia, causes other health problems / anaemia / tiredness;
Sufferers of sickle cell anemia have inherited two mutated recessive alleles

 

 

 

 

Extra Details

HBB: The Gene Associated with Sickle Cell Anemia

Chromosome 11
Approximate gene location is based on Chromosome 11 map from NCBI Entrez Map Viewer.

Official Gene Symbol: HBB

Name of Gene Product: hemoglobin, beta

Locus: 11p15.5 - The HBB gene is found in region 15.5 on the short (p) arm of human chromosome 11.

Gene Structure: The normal allelic variant for this gene is 1600 base pairs (bp) long and contains three exons.

Protein Size: The HBB protein is 146 amino acids long and has a molecular weight of 15,867 Da. See the annotated HBB protein sequence record in Swiss-Prot.

Protein Function: Hemoglobin molecules, in red blood cells, are responsible for carrying oxygen. The HBB gene codes for one of the two types of polypeptide chains found in adult haemoglobin. Normal adult hemoglobin is a protein consisting of two alpha chains and two beta chains. HBB codes for the beta chain, which is often referred to as beta globin. Mutant beta globin is responsible for the sickling of red blood cells seen in sickle cell anemia.

Sickle cell anaemia is most commonly caused by a base substitution mutation., The amino acid valine takes the place of glutamic acid at the sixth amino acid position of the polypeptide chain. This substitution causes the "sickling" of red blood cells.

Sickle cell anaemia is an autosomal recessive genetic disorder. For the disease to be expressed, a person must inherit either two copies of Hb S variant or one copy of Hb S and one copy of another variant. Carriers, who have one copy of the normal HBB gene (Hb A) and one copy of Hb S, are described as having sickle cell trait and do not express disease symptoms. To learn more about sickle cell anaemia, see the Disease Profile.