Table of Contents
- Point mutation definition
- Causes of Point mutation
- Mechanism of Point mutation
- Types of Point Mutations (based on the substitution of the base pairs)
- Types of Point Mutations (based on effects produced by the changes)
- Applications
- References
Point mutation definition
- Point mutation refers to a type of genetic mutation where a single base pair in the DNA sequence is altered, which can occur through the insertion or deletion of a base pair.
- As the name implies, a point mutation takes place at a specific point in the DNA sequence due to a change in one particular base pair.
- These mutations most commonly arise as a result of errors during the process of DNA replication.
- In addition to replication errors, point mutations can also be caused by external factors such as exposure to ultraviolet (UV) radiation or X-rays, which can modify the DNA structure.
- The consequences of point mutations vary depending on the specific nature and location of the mutation; their effects can range from having no impact to causing harmful changes that affect how proteins are produced, composed, or function.
- Point mutation is a structural type of mutation that affects chromosomes by altering the nucleotide sequence.
- Because nucleotides are read in triplets during protein synthesis, a point mutation can lead to changes in the amino acid sequence of a protein, potentially altering its structure and function.
- Furthermore, mutations occurring at the beginning or the end of a gene sequence can result in premature initiation or early termination of protein synthesis.
- Therefore, the severity and impact of a point mutation are largely dependent on the specific location within the gene where the mutation occurs.
Causes of Point mutation
- Most point mutations occur during DNA replication, where even a single change in the DNA sequence can alter the entire genetic code.
- A change in either a purine or a pyrimidine base can alter the amino acid that the nucleotide sequence codes for.
- These alterations may result from spontaneous mutations that naturally occur during DNA replication.
- However, the frequency of point mutations increases significantly with exposure to mutagens.
- Mutagens can be physical agents such as X-rays and ultraviolet (UV) radiation or chemical substances that modify base pairs and alter the DNA structure.
- In the case of radiation, the energy can ionize DNA molecules, leading to changes in the composition of the genetic sequence.
- Additionally, byproducts of cellular metabolism, such as reactive oxygen species (ROS), can damage specific base pairs within the DNA structure.
- Such mutations can affect both the single-stranded DNA and the double-stranded helical form of DNA.
- Some of these changes may also occur during the post-replication processing of DNA, when enzymes like nucleases digest or modify base pairs.
- Other types of mutations—such as deletions, substitutions, and insertions—can also contribute to the occurrence of point mutations at various stages of DNA formation, replication, and processing.
Mechanism of Point mutation
- Point mutations can occur through various mechanisms depending on the underlying cause of the mutation.
- In most cases, point mutations arise spontaneously during DNA replication, with nucleotide substitution being the most frequent mechanism involved.
Substitution
- The substitution of one base pair for another during DNA replication is the most common mechanism of point mutation.
- This often results from a tautomeric shift, where the hydrogen atoms within a nucleotide base change position, altering the bonding characteristics of the base.
- All four nucleotide bases in DNA can exist in alternative structural forms known as tautomers.
- These tautomers exist in dynamic equilibrium, with the keto form being the most stable and commonly found in DNA, while the enol forms are rare.
- A shift from the keto to the enol form can alter the typical base-pairing rules, leading to mismatched pairing and, consequently, point mutations.
- For instance, guanine in its enol form can pair with thymine instead of its correct partner, cytosine, causing a point mutation in the sequence.
Ionization
- Ionization is another key mechanism of point mutation and occurs due to the influence of chemical agents or radiation.
- DNA bases can undergo spontaneous ionization, transforming into forms that are unable to form proper hydrogen bonds with their complementary base pairs.
- This abnormal bonding can lead to mismatched pairings with other bases or molecules, resulting in sequence alterations and point mutations.
Types of Point Mutations (based on the substitution of the base pairs)
Point mutations can be categorized into two main types based on the substitution pattern of base pairs.
Transition mutations
- These mutations occur when a pyrimidine base (cytosine or thymine) is replaced by another pyrimidine, or when a purine base (adenine or guanine) is replaced by another purine.
- In double-stranded DNA, each base normally pairs with its specific complementary partner. Substitution of one nitrogenous base for another alters the pairing and leads to different base pair formations.
- Transition mutations commonly arise due to processes like oxidative deamination and tautomerization of the bases.
- These mutations are more frequently observed in genomes due to the ease of molecular mechanisms that facilitate their occurrence, despite there being only a single possible transition per base pair.
- Transition mutations are less likely to cause amino acid changes in proteins, making them more likely to appear as silent mutations, such as single nucleotide polymorphisms (SNPs), in genomic populations.
- Example: A transition mutation can occur when adenine is replaced by guanine or when cytosine is replaced by thymine and vice versa. In these examples, purines (adenine ↔ guanine) and pyrimidines (cytosine ↔ thymine) are exchanged within their respective categories.
Transversion mutations
- These mutations occur when a purine base is replaced by a pyrimidine base, or vice versa.
- Transversions are generally spontaneous but can also be triggered by external agents like radiation or alkylating chemicals. In cases of spontaneous mutation, transversions can sometimes be reversible.
- Although there are two main transversion types, they occur less frequently than transitions due to structural challenges—replacing a double-ring purine with a single-ring pyrimidine (or vice versa) is less compatible during replication.
- Transversions typically have a more significant impact on genetic information because the third nucleotide in a codon is less tolerant to such changes.
- As a result, transversions are more likely to result in codons that do not encode the same amino acid, thereby altering the resulting protein.
- Example: A transversion mutation can occur when a purine like adenine or guanine is substituted with a pyrimidine like thymine or cytosine. In total, eight possible transversion changes can occur between the two purines and two pyrimidines.
Types of Point Mutations (based on effects produced by the changes)
Point mutations can be classified into different types depending on the effects they produce on the resulting protein or phenotype.
1. Nonsense mutations
- A nonsense mutation (or point-nonsense mutation) occurs when a single base pair substitution results in a premature stop codon.
- This mutation replaces a codon that originally coded for an amino acid with a stop codon, abruptly halting protein synthesis.
- The severity of the mutation’s impact depends on the position of the premature stop codon. If it appears close to the original stop codon, the functional effect may be mild; if it occurs far from it, the resulting damage is typically greater.
- Nonsense mutations often produce truncated, nonfunctional proteins and are considered one of the most damaging types of point mutations.
Example of Nonsense mutation
- Beta thalassemias are an example of a disorder caused by point nonsense mutations affecting the gene that codes for the beta chains of hemoglobin.
- Depending on the mutation’s position, the effects range from severe anemia to being clinically asymptomatic.
- The mutation can occur through either a base substitution near the promoter region of the beta-globin gene or a deletion of nucleotides upstream of the gene.
- In both cases, the mutation leads to a premature stop codon that prevents proper formation of the globin protein.
2. Missense mutations
- A missense mutation is a type of point mutation in which a single base pair substitution results in the incorporation of a different amino acid into the resulting protein.
- The consequences of this mutation vary; it may result in a nonfunctional protein or have no significant effect, depending on the nature and location of the substitution.
- Missense mutations are associated with several diseases, such as Epidermolysis bullosa, amyotrophic lateral sclerosis (ALS), and sickle-cell disease.
- Not all missense mutations are harmful. In some cases, an amino acid is replaced by another with similar chemical properties, preserving protein function—these are often considered silent at the functional level.
- The position of the substitution within the gene also plays a major role in determining its impact on the protein’s structure and function.
Example of Missense mutation
- Sickle cell anemia results from a missense mutation where a different amino acid is incorporated, altering the structure of red blood cells.
- This change impairs the cells’ ability to carry oxygen and leads to complications like blood clotting.
- The mutation occurs upstream in the gene responsible for coding proteins that form the red blood cell membrane.
- The altered nucleotide sequence changes the amino acid composition, affecting the shape and function of the red blood cells.
3. Silent mutations
- Silent mutations are point mutations that have no observable effect on the phenotype of the organism.
- These mutations occur when a base pair is substituted but the resulting codon still codes for the same amino acid as the original codon.
- This is possible due to the redundancy of the genetic code, where multiple codons can code for the same amino acid.
- In some instances, even when the codon results in a different amino acid, if the new amino acid has similar chemical properties, the function and structure of the protein remain unchanged.
- As a result, silent mutations typically do not alter the final protein product.
Example of Silent mutation
- A silent mutation is observed when a thymine (T) is replaced by cytosine (C) in the TTC codon, producing the TTT codon.
- The corresponding mRNA codons are AAG and AAA, respectively—both of which code for the amino acid lysine.
- Although the DNA sequence changes, the resulting protein remains unchanged, and the mutation has no effect on the phenotype.
4. Frameshift mutations
- A frameshift point mutation involves the insertion or deletion of nucleotides in a way that shifts the reading frame of the genetic code.
- The severity of the mutation’s effect is dependent on its position—mutations occurring earlier in the sequence tend to have more drastic consequences.
- Frameshift mutations alter the grouping of nucleotides into codons, resulting in completely different amino acid sequences from the original, often producing a nonfunctional protein.
- These mutations frequently result in the formation of abnormal polypeptides that are either too long or too short.
- Frameshift mutations are among the most severe types of point mutations due to their potential to disrupt the entire downstream amino acid sequence.
Example of Frameshift mutation
- Crohn’s disease is linked to a frameshift mutation in the NOD2 gene.
- The mutation involves the insertion of a cytosine (C) nucleotide at position 3020 in the gene.
- This insertion changes the codon to a premature stop codon, producing a shortened protein.
- The abnormal protein is unable to properly recognize bacterial liposaccharides, disrupting immune responses.
- The mutation does not involve a change in multiples of three nucleotides, which is what causes the shift in the reading frame and leads to the disease.
Applications of Point Mutations
- Point mutations have several important applications with both industrial and medical significance.
- They can be utilized to modify specific genes involved in disease development as part of molecular therapy, offering potential treatments for various genetic disorders.
- Certain mutagens are used to deliberately target and induce point mutations in cancer cells, allowing for the selective removal or alteration of specific nucleotides within tumor DNA.
- Mutational breeding employs mutagens to induce beneficial point mutations in plants, leading to the development of improved crop varieties with enhanced yield, disease resistance, or stress tolerance.
- In the case of heritable mutations, point mutations can be introduced to incorporate favorable traits into organisms, which can be passed on to future generations and used across biotechnology, agriculture, or pharmaceutical industries.
References
- Griffiths, A. J. F., Gelbart, W. M., Miller, J. H., et al. (1999). Modern Genetic Analysis: The Molecular Basis of Mutation. New York: W. H. Freeman. Available at: NCBI Bookshelf
- Verma, P. S., & Agarwal, V. K. (2005). Cell Biology, Genetics, Molecular Biology, Evolution and Ecology. Multicoloured Edition.
- Beck-Engeser, G. B., et al. (2001). Point mutation in essential genes with loss or mutation of the second allele: relevance to the retention of tumor-specific antigens. The Journal of Experimental Medicine, 194(3), 285–300. https://doi.org/10.1084/jem.194.3.285
- Tan, X., et al. (2015). Clinical significance of a point mutation in DNA polymerase beta (POLB) gene in gastric cancer. International Journal of Biological Sciences, 11(2), 144–155. https://doi.org/10.7150/ijbs.10692
- Sun, X., et al. (2006). Point mutations with positive selection were a major force during the evolution of a receptor-kinase resistance gene family of rice. Plant Physiology, 140(3), 998–1008. https://doi.org/10.1104/pp.105.073080