There are a number of mutations affecting the production of fetal haemoglobin, HbF, and normal adult haemoglobin, HbA. • The HbA allele codes for the normal ẞ-globin polypeptide of haemoglobin. • The HbS allele, caused by a base substitution mutation, codes for an abnormal ẞ-globin polypeptide. • The base substitution results in the amino acid glutamine, which has a polar R group, to be replaced by valine, which has a non-polar R group, in the polypeptide. The abnormal haemoglobin molecules (HbS) form fibres in low partial pressures of oxygen (p02). The fibres cause red blood cells to become sickle shaped and the cells can block blood capillaries. Individuals with adult haemoglobin molecules that are all abnormal (HbS) have sickle cell anaemia.

1. (a)Explain why this mutation causes the HbS to form fibres.[2]
2. (b)(i)Fetal haemoglobin, HbF, is produced by the fetus until just before birth, when adult haemoglobin begins to be made. By the age of six months, adult haemoglobin has replaced most of the HbF. This change occurs when the genes coding for HbF are switched off and the genes coding for adult haemoglobin are switched on. : • A base substitution, British-198, causes fetal haemoglobin to continue to be produced. • Normally by the age of six months, the concentration of HbF reduces to less than 1% of total haemoglobin. • With the British-198 mutation, the concentration of HbF may be as high as 20% of total haemoglobin in an adult. • HbF has a higher affinity for oxygen at low pO2 than adult haemoglobin. Individuals who have both sickle cell anaemia and British-198 mutation have reduced symptoms of sickle cell anaemia. Suggest why having the British-198 mutation reduces the symptoms of sickle cell anaemia.[2]
3. (b)(ii)In adults with the British-198 mutation, the gene coding for a fetal haemoglobin polypeptide remains switched on. This is due to the presence of a protein that controls gene expression. State the term that is used to describe a protein that controls gene expression.[1]
4. (c)(i)Gel electrophoresis can be carried out to test individuals for the different versions of haemoglobin: HbA, HbS and HbF. : A buffer with alkaline pH is used to make all haemoglobin molecules negatively charged. HbS molecules have an additional positive charge compared to HbA. Describe and explain how gel electrophoresis is used to diagnose sickle cell anaemia.[4]
5. (c)(ii)Four individuals had their haemoglobin analysed by gel electrophoresis. One of the individuals was heterozygous for the HbA and HbS alleles and had a condition known as sickle cell trait (SCT). Some of the results are shown in Fig. 4.1. In Fig. 4.1, lane 1 and lane 5 are complete. [Figure 4.1] Predict the results for the individuals analysed, by adding bands to lanes 2, 3 and 4 on Fig. 4.1.[2]

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