Molecular nature and allelic variants
The phenomenon is based on allelic variants of genes. These are forms of a gene that occupy strictly homologous loci in chromosomes. The main feature of allelic variants is that they encode proteins with a very similar spatial structure and analogous functions. In essence, such proteins represent polymorphic varieties of a single protein.
At the molecular level, polymorphism represents small deviations in the nucleotide sequence of DNA. Importantly, such mutations are fully compatible with the normal functioning and development of the organism at all stages of ontogenesis.
Types of genetic polymorphism
Changes in genetic material can affect both coding regions (exons) and non-coding regions (introns). Two main types of such changes are distinguished:
- Qualitative polymorphism — caused by point substitutions of nucleotides in the DNA chain.
- Quantitative polymorphism — associated with variation in the number of nucleotide repeats, which can vary significantly in length.
Biochemical individuality and variability
Genetic polymorphism serves as the fundamental basis for the formation of ethnic and individual genome differences. The scale of this phenomenon differs drastically at the level of an individual versus an entire group:
- In an individual, genetic variability is strictly limited: a maximum of two different variants can be present for any given protein.
- In the human population, the number of such variants can be truly immense. A classic example is hemoglobin HbA, for which more than 600 genetically distinct groups have been described.
Precisely because protein polymorphism is so vast, biochemical individuality of the person is formed. The genomes of all people on the planet are unique and have their own specific differences. The only exception to this rule is monozygotic twins, whose genomes are completely identical.
Briefly: answers to topical questions
What methods are used to detect genetic polymorphism in the laboratory?
To detect genetic polymorphism in laboratory practice, modern molecular-genetic DNA analysis technologies are used. The main tools are:
- Polymerase chain reaction (PCR) — allows direct identification of genes and multiple amplification of specific regions.
- Restriction fragment length polymorphism (RFLP) — analysis of changes in DNA fragment sizes after treatment with restriction endonucleases.
- Sequencing — direct determination of the nucleotide sequence of genes.
- Allele-specific probes — detection of mutations using molecular probes.
- Direct detection — direct discovery of mutant genes.
Give examples of multifactorial diseases associated with genetic polymorphism.
Genetic polymorphism is indicated in sources as one of the components of genetic predisposition in a number of multifactorial diseases and disease groups. Examples:
- Crohn's disease — exact etiology not established; the disease is multifactorial, with about 100 associated genetic polymorphisms described.
- Hypertension — a multifactorial disease with a polygenic hereditary predisposition; polymorphisms of genes determining RAAS activity, sympathetic reactivity, renal sodium transport, endothelial function, and vascular wall structure are inherited.
- Autoimmune diseases — considered multifactorial; genetic predisposition is associated with certain HLA antigens and cytokine gene polymorphisms.
- Rheumatoid arthritis — GWAS identified over 100 single nucleotide polymorphisms associated with the risk of RA development and progression; the main genetic risk factor is carriage of HLA-DR01/04.
What is the role of enzyme genetic polymorphism in drug pharmacokinetics?
Genetic polymorphism of drug-metabolizing enzymes, especially cytochromes P450, leads to differences in amino acid sequences, altered enzyme specificity/activity, and individual drug responses.
For CYP2D6, sources describe pronounced interindividual variability in nebivolol metabolism; metoprolol is also metabolized by CYP2D6, and the rate of its metabolism is individual.
| Metabolism type | Confirmed pharmacokinetic and clinical features |
|---|---|
| Extensive metabolizers | High enzyme activity; for nebivolol — intensive presystemic metabolism, low bioavailability (~12%), T1/2 about 10 hours. |
| Poor metabolizers | For nebivolol — bioavailability is almost complete (~96%), T1/2 30–50 hours, cardioselectivity is significantly lower. For metoprolol in poor metabolizers, the risk of side effects is approximately 5 times higher. |
Sources also indicate that variants of the DPYD gene are associated with toxicity of pyrimidine analogues (5-fluorouracil, capecitabine), while UGT1A1 polymorphism is associated with toxicity of irinotecan class drugs.
Class and exam questions
What are protein allelic variants?
These are polymorphic varieties of the same protein. They are encoded by genes that occupy strictly homologous loci in chromosomes.
What is the difference between qualitative and quantitative polymorphism?
Qualitative polymorphism arises due to the substitution of individual nucleotides in the DNA sequence. Quantitative polymorphism manifests as variation in the number of nucleotide repeats of various lengths.
Whose genomes completely match?
Due to colossal genetic polymorphism, the genomes of all people are diverse and unique. The only exception is monozygotic twins.
What else to study on this topic
- The mutational process as the basis of ethnic and individual differences
- Exonic and intronic DNA sequences in polymorphism
- The role of polymorphism in normal human ontogenesis
- Multiplicity of hemoglobin HbA variants in the population
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