Gene mutations

Main mechanisms of gene structure alteration

Mutations at the gene level are realized through several basic molecular scenarios:

• Base substitution. Most often occurs in the coding part of an exon directly during DNA replication.
• Frameshift. A change in the initial number of nucleotide pairs. It occurs via deletion (loss of a segment) or duplication (its doubling).
• Inversion. Rotation of the nucleotide sequence within a structural gene by exactly 180°. Notably, the reading frame does not shift with such a rotation.
• Splicing mutations. Point substitutions localized at the exon-intron boundaries. They disrupt the crucial process of nucleotide sequence splicing during RNA maturation.
• Dynamic mutations. An expansion process in which the number of specific triplet repeats (e.g., CTT or CGG) uncontrollably increases. This can affect both coding and non-coding DNA regions.
• Insertion. Incorporation of mobile elements (transposons) into a gene.

Molecular level: types of substitutions and their consequences

At the molecular level, all simple nitrogenous base substitutions are divided into two major classes. Transitions (simple substitutions) are characterized by the replacement of a purine with another purine (e.g., adenine with guanine) or a pyrimidine with a pyrimidine (thymine with cytosine). Transversions (cross-substitutions) are rearrangements in which a purine base is replaced by a pyrimidine, or vice versa.

Any such substitution leads to the formation of one of three types of mutant codons that determine the further fate of the protein:

1. Missense mutations (missense — loss of sense). The meaning of the genetic code changes, and a completely different amino acid is incorporated into the growing polypeptide chain.
2. Neutral mutations. Synonymous substitutions occur. Due to the degeneracy of the genetic code, a base change does not entail a change in the properties of the synthesized molecule — the functional activity of the protein is preserved.
3. Nonsense mutations (nonsense — nonsense). A stop codon suddenly appears within the structural gene. This leads to premature termination: the polypeptide chain is truncated, and the synthesized proteins become unable to perform their direct functions.

Frameshift

The reading frame is a strict sequence of nucleotides from the initiation to the termination codon, consisting of triplets that encode amino acids. The frameshift mechanism is triggered by insertions, duplications, deletions, or base shifts.

The essence of the phenomenon is that the mutation fatally alters all triplets located after the alteration point. The main result of such a shift is a sharp increase in the probability of accidental stop codons and, consequently, premature termination of translation.

Frameshifts can be caused by:

• Chemical agents: for example, acridine compounds. They cause spatial deformation of the DNA double helix structure, which provokes the insertion or loss of nucleotides during replication.
• Physical factors: exposure to X-ray radiation (very frequently causes multiple deletions).
• Mobile genetic elements: prokaryotic and eukaryotic transposons are extended nucleotide sequences. They are capable of spontaneously changing their position in the genome, and their integration generates insertion-type mutations.

Clinical examples of gene mutations

A classic example of high functional divergence of genes is provided by globin genes, where more than 300 different point amino acid substitutions have been identified.

• Sickle cell anemia (SCA). The disease is caused by a substitution in the 6th triplet of the alpha-globin gene. The molecular mechanism consists of replacing adenine with thymine (the GAG codon changes to GTG). This leads to the replacement of the amino acid glutamine with valine. Homozygous carriers of this trait develop SCA.
• Hemoglobin Cranston (Hemoglobin Cranston). The disease is caused by the insertion of two nucleotides in the 145th triplet of the beta-globin gene. A frameshift occurs: the normal stop codon UAA turns into the coding ACU. Chain synthesis does not stop, 11 additional amino acids are added (the chain lengthens to 157 amino acids). As a result, an extremely unstable hemoglobin is formed.
• Cystic fibrosis. The cause is a point mutation in the form of a deletion of three adjacent nucleotides at position 508. The consequence is the loss of an amino acid critically important for the function of the resulting protein.
• Beta-thalassemia. The pathology is due to other globin gene mutations leading to the appearance of corresponding clinical alleles.

Briefly: answers to topical questions

Class and exam questions

What else to study on this topic

• Mechanisms of trinucleotide repeat expansion in dynamic mutations
• The effect of splicing mutations on mRNA maturation processes
• Interaction of acridine compounds with the structure of the DNA double helix
• The role of transposons in the evolution of eukaryotic genomes

Other topics in the "Variability and its forms" section

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