Gene mutations

Types of DNA-level changes

Any gene mutation begins with a rearrangement of the nucleotide sequence. Several basic variants of such structural changes are distinguished:

• Deletion is the physical loss of a fragment of genetic material.
• Duplication is the abnormal doubling or repeated duplication of a specific DNA segment.
• Inversion is the rotation of a chain segment by exactly 180 degrees.
• Insertion is the integration (insertion) of an additional fragment into the original chain.

Point substitutions of nitrogenous bases in codons are classified separately:

• Transition occurs when a purine base is replaced by another purine, or a pyrimidine by a pyrimidine.
• Transversion is a cross-substitution of a purine for a pyrimidine or vice versa.

Impact on protein synthesis and phenotype

Changes in DNA structure inevitably affect the translation process. Depending on the consequences for the protein molecule, five types of mutations are distinguished:

1. Neutral ("silent") mutations. They have no external manifestation. Due to the degeneracy of the genetic code, the altered codon often encodes the same amino acid, so the protein structure remains unaffected.
2. Missense mutations. A point substitution of a nucleotide in the coding region leads to the incorporation of a different amino acid. As a result, a polypeptide with altered properties is synthesized.
3. Nonsense mutations. The substitution of a nitrogenous base forms a stop codon (terminator codon). Protein synthesis is prematurely truncated, and translation stops.
4. Regulatory mutations. They are localized in the 5'- or 3'-untranslated regions. The gene itself remains intact, but the regulation of its expression is disrupted.
5. Dynamic mutations. They arise due to a pathological increase in the number of trinucleotide repeats in functionally significant parts of the gene. This can completely block transcription or impart properties to the protein that disrupt its normal metabolism.

Classification by outcomes and cell types

The severity of consequences for the organism depends on which cells experienced the malfunction and how critical the defect turned out to be.

Based on the localization of the primary defect, the following are distinguished:

• Germline mutations. They occur in germ cells, are inherited, and form true hereditary diseases (e.g., hemophilias or phenylketonuria).
• Somatic mutations. They arise in body cells and are not transmitted to offspring. They frequently cause the development of tumors or certain autoimmune diseases.
• Combined mutations. They combine mutations in both germ and somatic cells (an example is familial retinoblastoma).

According to the clinical outcome, pathologies are divided into:

• Lethal mutations. They lead to death during the embryonic development stage (haploidy, autosomal monosomies, most polyploidies).
• Sublethal mutations. They result in death before the pubertal period, precluding reproduction (Louis-Bar syndrome, certain hemophilias, Swiss-type agammaglobulinemia).
• Hypogenital mutations. They are combined with infertility (Klinefelter and Turner syndromes).

Monogenic diseases

Hereditary forms of pathology are transmitted to children from parents via germ cells and always have a pedigree. The most common form of gene diseases is monogenic disorders.

They are typically differentiated by which specific functional class of polypeptide is affected:

• Structural proteins.
• Enzyme proteins (leading to enzymopathies).
• Receptor proteins.
• Transmembrane transporters.

The key characteristic of any monogenic disease is its type of inheritance. It can be autosomal dominant, autosomal recessive, X-linked (dominant or recessive), holandric (Y-linked), or mitochondrial. It is important to remember that in recessive inheritance, the heterozygote phenotype may not differ from normal—disease manifestations will be mild or completely absent.

Briefly: answers to topical questions

Class and exam questions

What else to study on this topic

• Genomic mutations: polyploidy and aneuploidy
• Mechanisms of non-multiple chromosome number changes (nondisjunction and anaphase lag)
• Classification of diseases by the role of hereditary and environmental factors
• Ecogenetic diseases and diseases of genetic predisposition
• Chromosomal diseases in the structure of hereditary pathologies

Other topics in chapter "Chapter 3. Forms of pathology caused by changes in the genome"

Prepared by WhiteCoat Pro faculty in accordance with the medical school curriculum. For educational purposes only.