79 Heterozygous Advantage

Key Idea: Heterozygous advantage is a phenomenon in which the heterozygote has a greater fitness than either of the homozygotes in certain selective environments. Natural selection operates on phenotypes (and therefore their genotypes) in the prevailing environment. For some phenotypic conditions controlled by a single gene with two alleles, a heterozygote (an individual with two different alleles for a gene) may have a higher fitness than either of the homozygous conditions. This situation is called heterozygous advantage. In the case of the sickle cell allele outlined below, susceptibility to malaria is high in the homozygous dominant condition, but lower in the heterozygous condition. Consequently, the heterozygote has a higher fitness in malaria-prone regions. Heterozygous advantage can result in the stable coexistence of different phenotypes in a population (a state called balanced polymorphism) and can account for the persistence of detrimental alleles. The maintenance of the sickle cell mutation in malaria-prone regions is one of the few well documented examples in which the evidence for heterozygous advantage is conclusive.

The sickle cell allele (HbS)

Sickle cell disease is caused by a mutation in a gene encoding haemoglobin. Genetic analyses show that the mutation arose spontaneously in different regions. The mutant allele (HbS) produces a form of haemoglobin that differs from the functional form by just one amino acid in the b-chain. This small change causes 'sickling' of the red blood cells. The sickling causes the red blood cells to clump together, blocking blood vessels, and causing numerous circulatory and organ problems. Destruction of the red blood cells also leads to anaemia. ` In heterozygotes (HbSHb), there is a mixture of both normal and sickle cells and they are said to carry the sickle cell trait. They are generally unaffected by the disease except in low oxygen environments. ` People with two HbS genes (HbSHbS) suffer severe illness and often die prematurely. HbS is therefore considered to be a lethal allele.

Heterozygous advantage in malarial regions

Falciparum malaria is widely distributed throughout central Africa, the Mediterranean, Middle East, and tropical and semi-tropical Asia (Fig. 1). It is transmitted by the Anopheles mosquito, which spreads the protozoan Plasmodium falciparum from person to person as it feeds on blood. Symptoms appear 1-2 weeks after being bitten, and include headache, shaking, chills, and fever. Falciparum malaria is more severe than other forms of malaria, with high fever, convulsions, and coma. Death can occur within days of the first symptoms appearing. The paradox: The HbS allele offers considerable protection against malaria. Sickle cells have low potassium levels, which causes Plasmodium parasites inside these cells to die. Those with a normal phenotype are very susceptible to malaria, but heterozygotes (HbSHb) are much less so. This situation, called heterozygous advantage, has resulted in the HbS allele being present in moderately high frequencies in parts of Africa and Asia despite its harmful effects (Fig. 2). This is a special case of balanced polymorphism, called a balanced lethal system because neither of the homozygotes produces a phenotype that survives, but the heterozygote is viable.

Areas affected by falciparum malaria

Four species of Plasmodium cause malaria but the variety caused by P. falciparum is the most severe. Anopheles mosquito, the insect vector responsible for spreading Plasmodium.

Fig. 1: Incidence of falciparum malaria

1% - 5%

5% - 10%

10% - 20%

HbHb

All red blood cells normal Susceptible to malaria

HbsHb

Normal and sickle cells Malaria resistance

HbsHbs

All cells are sickled Sickle cell disease

Fig. 2: Frequency of the sickle cell allele

1. Why do carriers of the Hbs allele have an advantage in malaria-prone regions?

3. (a) Describe the distribution of malaria throughout the world (Figure 1):

(b) What do you notice about its distribution compared to the frequency of the Hbs allele (Figure 2)?

4. Describe the distribution of red blood cell abnormalities (Figure 3) and explain why these abnormalities persist:

Figure 3 shows the general distributions of various haemoglobin disorders that all produce abnormal red blood cells to some degree. HbE is a mutation that appears to have arisen about 5000 years ago and is caused by a change in the 26th amino acid in the b-chain from glutamic acid to lysine. The HbS mutation changes the 6th amino acid from glutamic acid to valine. HbC is a mutation that occurs in the same position as HbS, but the mutation produces the amino acid lysine instead of valine. Both HbE and HbC heterozygotes show virtually no (and certainly much less than HbS) symptoms of anaemia (reduced haemoglobin levels). Thalassaemia is a disease in which gene mutations result in the lowered production of haemoglobin and red blood cells. The effects can be very severe.

HbE

HbS

HbC

Thalassaemia

Fig. 3: : Distribution of abnormal blood conditions