Genetic polymorphism and natural selection
To date, a tremendous number of genetic variants of the erythrocyte protein circulate in human populations—there are more than 400 hemoglobin synthesis alleles. Of greatest clinical and evolutionary interest are abnormal hemoglobins designated by the letters S, C, D, and E.
The high frequency of these abnormal proteins in populations serves as a classic illustration of how natural selection works by maintaining balanced genetic polymorphism. This means that the presence of a mutation, despite its pathogenic potential, ensures population survival under severe environmental stress.
Hemoglobin S (HbS) and sickle cell anemia
The HbS variant underlies the development of severe pathology—sickle cell anemia. This mutation is believed to have arisen approximately 2,000–3,000 years ago and is now most widespread in parts of Africa.
- Genetic defect: A point mutation in the protein structure replaces normal amino acid (glutamic acid) with valine.
- Pathogenesis: The appearance of valine forms hydrophobic residues. These regions actively interact with valine on an adjacent protein chain, leading to hemoglobin polymerization. As a result, the erythrocyte itself deforms and takes on a characteristic sickle shape.
- Advantage: Despite the development of anemia, carrying HbS confers a massive selective advantage. In heterozygous carriers, fatal outcomes from falciparum malaria are prevented in 90% of cases.
Hemoglobins C and E: substitution with lysine
Unlike sickle cell anemia, mutations leading to the formation of hemoglobins C and E involve the replacement of glutamic acid with another amino acid — lysine.
Hemoglobin C (HbC): Its main feature is a pronounced dose-dependent protective effect against malaria. In the heterozygous state, the mutation provides 30% protection. However, in the homozygous state (HbC/HbC genotype), protection against infection rises to an impressive 90%.
Hemoglobin E (HbE): In this variant, the substitution of glutamic acid with lysine occurs strictly at the 26th position of the amino acid sequence.
- Epidemiology: The mutation appeared in the human population relatively recently, but is characterized by an extremely high spread rate. In Southeast Asian countries, the proportion of carriers reaches 50%.
- Clinical significance: Homozygotes for HbE suffer from an asymptomatic form of anemia while acquiring valuable resistance to vivax malaria.
Hemoglobin H (HbH) and thalassemia
Hemoglobin H is associated with a fundamentally different mechanism of genetic abnormality. While previous forms are caused by amino acid substitutions, this involves a disruption in the quantity of synthesized chains.
- Essence of the mutation: There is a partial suppression of the synthesis of the alpha-chain of the hemoglobin molecule.
- Clinical presentation: A severe disease develops—thalassemia, also known as Cooley's anemia. The prognosis for this pathology is extremely unfavorable; it is a fatal congenital disease.
- Laboratory diagnostics: Diagnosis is confirmed by blood smear microscopy. A characteristic feature is the presence of erythrocytes of unusual shape and abnormal size, with critically low hemoglobin content.
Briefly: answers to topical questions
What laboratory methods are used for precise identification of abnormal hemoglobin fractions?
Methods for detecting abnormal hemoglobin are listed in the source in order of increasing diagnostic efficiency:
- hypoxic test — to detect sickle cells;
- hemoglobin electrophoresis;
- capillary hemoglobin electrophoresis — to identify hemoglobin types;
- high-performance liquid chromatography — for quantitative assessment of hemoglobin type ratios.
Capillary electrophoresis or HPLC are also indicated for initial screening laboratory diagnostics.
To memorize amino acid substitutions: HbS stands for Sickle shape, substitution with Valine (S/V). In HbC and HbE variants, glutamic acid is replaced by Lysine (CE/L).
Class and exam questions
What is balanced genetic polymorphism using erythrocytes as an example?
This is an evolutionary compromise where mutant alleles (e.g., genes for abnormal hemoglobins) are not washed out of the population. They are preserved because their presence gives carriers a powerful advantage—resistance to endemic diseases such as malaria.
Why do erythrocytes change shape in the presence of hemoglobin S?
The basis is the substitution of glutamic acid with valine. The resulting hydrophobic valine residues bind to valine on the adjacent protein chain, causing hemoglobin to polymerize and mechanically stretch the cell into a sickle shape.
How do the effects of HbC and HbE mutations differ from the pathogenesis of HbS?
In both cases, glutamic acid is replaced by lysine rather than valine. They less frequently cause severe erythrocyte deformation; HbE homozygotes have only asymptomatic anemia, while HbC homozygotes are 90% protected against malaria.
How is thalassemia rapidly diagnosed in the laboratory?
The basis of primary diagnosis is the evaluation of a blood smear. The specialist detects abnormally shaped and sized erythrocytes characterized by abnormally low hemoglobin saturation.
What else to study on this topic
- Pathogenesis of intravascular polymerized hemoglobin in HbS
- Genetic basis of alpha-chain synthesis suppression in thalassemia
- Differences in protection against falciparum and vivax malaria
- Distribution and clinical significance of hemoglobin D
- Mechanisms of asymptomatic anemia formation in the HbE mutation
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