GENE MUTATIONS: WHAT THEY CONSIST OF, TYPES AND CONSEQUENCES - BIOLOGY - 2025

The gene mutations or specific are those in which one allele of a gene change, becoming different one. This change occurs within a gene, at a locus or point, and can be located.

On the contrary, in chromosomal mutations, sets of chromosomes, an entire chromosome or segments of it are usually affected. They do not necessarily involve gene mutations, although it could occur in the case of chromosome breaks that affect a gene.

Figure 1. Mutation in a gene that controls the shape of the mouse tail. Source: By (Photograph courtesy of Emma Whitelaw, University of Sydney, Australia.), Via Wikimedia Commons

With the development of molecular tools applied to DNA sequencing, the term point mutation was redefined. Today this term is often used to refer to alterations in a pair or a few adjacent nitrogenous base pairs in DNA.

What are mutations?

Mutation is the quintessential mechanism that introduces genetic variation in populations. It consists of the sudden change in the genotype (DNA) of an organism, not due to recombination or genetic rearrangement, but due to inheritance or the effect of negative environmental factors (such as toxins and viruses).

A mutation can transcend the offspring if it occurs in germ cells (eggs and sperm). It can cause small variations in the individual, enormous variations - even causing diseases - or they can remain silent, without any effect.

Variations in the genetic material can then generate phenotypic diversity in nature, be it between individuals of different species or even of the same species.

Types of gene or point mutational changes

There are two types of gene mutational changes:

Nitrogen base changes

They consist of the substitution of one pair of nitrogenous bases for another. They are in turn divided into two types: transitions and transversions.

• Transitions: involve the substitution of one base for another of the same chemical category. For example: a purine for another purine, adenine for guanine or guanine for adenine (A → G or G → A). It can also be the case of substituting a pyrimidine for another pyrimidine, for example: cytosine for thymine or thymine for cytosine (C → T or T → C).
• Transversions: are changes that involve different chemical categories. For example, the case of change from a pyrimidine to a purine: T → A, T → G, C → G, C → A; or a purine for a pyrimidine: G → T, G → C, A → C, A → T.

By convention, these changes are described with reference to double-stranded DNA, and therefore the bases that make up the pair must be detailed. For example: a transition would be GC → AT, while a transversion could be GC → TA.

Figure 2. Types of point mutational changes. Source: (By Sara - Own work, CC BY-SA 3.0,

Insertions or deletions

They consist of the entry or exit of a pair or multiple pairs of nucleotides of a gene. Although the unit that is affected is the nucleotide, we usually always refer to the pair or pairs of bases involved.

Consequences

-Basic concepts

To study the consequences of gene mutations, we must first review two fundamental properties of the genetic code.

1. The first is that the genetic code is degenerate. This means that the same type of amino acid in the protein can be encoded by more than one triplet or codon in the DNA. This property implies the existence of more triplets or codons in DNA than types of amino acids.
2. The second property is that genes possess stop codons, used for the termination of translation during protein synthesis.

-Scenarios of gene mutations

Strut mutations can have different consequences, depending on the specific place where they occur. Therefore, we can visualize two possible scenarios:

1. The mutation occurs in a part of the gene in which the protein is encoded.
2. The mutation occurs in regulatory sequences or other types of sequences not involved in determining the protein.

-Functional consequences of the first scenario

Gene mutations in the first scenario generate the following results:

Silent mutation

It happens when a codon changes for another that codes for the same amino acid (this is a consequence of the degeneracy of the code). These mutations are called silent, because in real terms the resulting amino acid sequence does not change.

U-turn mutation

It occurs when the codon change determines an amino acid change. This mutation can have different effects depending on the nature of the new amino acid introduced.

If it is chemical in nature similar to the original (synonymous substitution), the effect on the functionality of the resulting protein may be negligible (this type of change is often called a conservative change).

When, on the other hand, the chemical nature of the resulting amino acid is very dissimilar to the original, the effect can be variable, and the resulting protein can be rendered useless (non-conservative change).

The specific location of such a mutation within the gene can have variable effects. For example, when the mutation occurs in part of the sequence that will give rise to the active center of the protein, the damage is expected to be greater than if it occurs in less critical regions.

Nonsense mutation

It happens when the change generates a translation stop codon. This type of mutation usually produces difunctional proteins (a truncated protein).

Insertions or deletions

They have an effect equivalent to the nonsense mutation, although not identical. The effect occurs when the DNA reading frame changes (a phenomenon known as reading frame shift or frameshift).

This variation produces a messenger RNA (mRNA) with a lag from the place where the mutation (insertion or deletion) occurred, and therefore a change in the protein amino acid sequence. The protein products obtained from genes with these types of mutations will be totally dysfunctional.

Exceptions

An exception could result when insertions or deletions of exactly three nucleotides (or multiples of three) occur.

In this case, despite the change, the reading frame remains unchanged. However, it cannot therefore be ruled out that the resulting protein is dysfunctional, either due to the incorporation of amino acids (in the case of insertion) or due to their loss (in the case of deletions).

-Functional consequences of the second scenario

Mutations can occur in regulatory-like sequences or other sequences not involved in determining proteins.

In these cases, the effect of the mutations is much more difficult to predict. It will then depend on how the point mutation affects the interaction of that fragment of DNA with the multiple regulators of gene expression that exist.

Again, the breaking of the reading frame or the simple loss of a fragment necessary for the binding of a regulator, can cause effects that range from the dysfunctionality of the protein products, to the lack of control in the amounts of the same.

-Frequent cases that lead to diseases

An example of a very rare point mutation is the so-called gain-of-sense mutation.

This consists of the transformation of the stop codon into a coding codon. This is the case of a variant of hemoglobin called Constant Spring Hemoglobin (allelic variant HBA2 * 0001), caused by the change of the stop codon UAA to the codon CAA.

In this case, the point mutation results in an unstable α-2 hemoglobin extended by 30 amino acids, causing a blood disease called alpha-thalassemia.

References

1. Eyre-Walker, A. (2006). The Distribution of Fitness Effects of New Deleterious Amino Acid Mutations in Humans. Genetics, 173 (2), 891–900. doi: 10.1534 / genetics.106.057570
2. Hartwell, LH et al. (2018). Genetics from Genes to Genomes. Sixth edition, MacGraw-Hill Education. pp.849
3. Novo-Villaverde, FJ (2008). Human Genetics: Concepts, mechanisms and applications of Genetics in the field of Biomedicine. Pearson Education, SA pp. 289
4. Nussbaum, RL et al. (2008). Genetics in Medicine. Seventh edition. Saunders, pp. 578.
5. Stoltzfus, A., and Cable, K. (2014). Mendelian-Mutationism: The Forgotten Evolutionary Synthesis. Journal of the History of Biology, 47 (4), 501–546. doi: 10.1007 / s10739-014-9383-2