Hemoglobin Variants

Ongoing Evolution - Evidence for the ongoing evolution of hemoglobin genes can be seen in the existence of numerous hemoglobin variants. Mutation positions of mutant hemoglobins in the human population are shown in Figure 7.25. Most proteins in existing plants and animals probably show comparable diversity.

Each of the mutant forms of hemoglobin exists in only a small fraction of the total human population. Many of the mutant forms are deleterious. Others appear to be harmless, and are often referred to as neutral mutations. A very few may have advantages. Inheritance of globin genes occurs as a result of standard genetic processes (see here for a review of genetics).

Pathological Effects - Deleterious mutations (Table 7.2) are mostly clustered about the heme pockets and in the vicinity of the - contact region that is so important in the allosteric transition (Figure 7.25).

Sickle-Cell Hemoglobin - Sickle-cell hemoglobin has gained its name because it causes red blood cells to adopt an elongated, sickle shape at low oxygen concentrations, due to the tendency of the mutant hemoglobin, in its deoxygenated state, to aggregate into long, rodlike structures. The elongated cells tend to block capillaries, causing inflammation and considerable pain. Even more serious is that the sickled cells are fragile. Their breakdown leads to an anemia that leaves the victim susceptible to infections and diseases. Individuals who are homozygous for the sickle-cell mutation often do not survive into adulthood, and those who do are seriously debilitated.

Sickling Mechanism - Remarkably, sickling stems from an apparently innocuous mutation in a part of the molecule far from the critical regions of the heme pockets and the / contact regions (Figure 7.21a). The Glutamate residue normally found at position 6 in chains is replaced by a valine (see Figure 7.21a). Valine is small (and hydrophobic) and can fit into a pocket at the EF corner of a chain in another hemoglobin molecule. Thus adjacent hemoglobin molecules can fit together into a long, rodlike helical fiber. Sickling occurs with deoxyhemoglobin, but not with oxyhemoglobin, because the rearrangement of subunits in the oxy form makes the EF pocket inaccessible.

Sickle Cell Advantage - Individuals heterozygous for sickle-cell hemoglobin have a higher resistance to malaria than those who do not carry the sickle-cell mutation. The malarial parasite spends a portion of its life cycle in human red cells, and the increased fragility of the sickled cells, even in heterozygous individuals, tends to interrupt this cycle. Heterozygous individuals have a higher survival rate-and therefore a better chance of passing on their genes-in malaria-infested regions. However, the high incidence of these genes in the population leads to the birth of many people who are homozygous for the mutant trait.

See also: Evolution of Myoglobin/Hemoglobin Proteins, Thalassemias, Hemoglobin

INTERNET LINKS:

> 1. Thalassemia Overview

> 2. Sickle Cell Disease

> 3. Hemoglobin Overview

> 4. Globin Gene Server