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At the simplest level, a mutation is a change or transformation. In biology, mutations refer to changes in chromosomes and genes, which typically manifest physically.

The effect of a mutation can depend on the region in which the sequence of genetic material has been changed. The simplest and the most harmless are substitutions of a single base pair with another, with no effect on the protein sequence. At the other end are insertion or deletion mutations that lead to non-functional gene products. Mutations can also occur on a large scale, with long stretches of DNA (or RNA when it is the genetic material) being inverted, inserted, duplicated, deleted, transposed or translocated.

The result of a mutation could be harmful, beneficial, neutral or even silent. Mutation can lead to the loss or gain of a specific function, to changes to the expression levels, or in extreme cases, even embryonic lethality.

Types of Mutation

Point mutations (also substitutions) are mutations that alter only one base in the DNA sequence. They may be transitions, where a purine is replaced by another purine (or the same for a pyrimidine): for instance a G to A mutation. Alternatively, they may be transversions, where a purine is replaced by a pyrimidine or vice versa: for instance a G to C mutation. Transitions are more common than transversions since purines and pyrimidines are structurally distinct so the substitution of one for another has a significant steric effect on the DNA helix which is more easily recognised by the proof-reading machinery.

Point mutations, whether transitions or transversions have no effect on the reading frame of the sequence.

Point mutations can be further classified according to their direct impact on the protein product:

  • Silent mutations (also synonymous mutations) are base changes that have no effect on the amino acid coded for. This is due to the degeneracy of the genetic code
  • Neutral mutations are base changes that substitute an amino acid for a different amino acid, but one of similar chemical properties. For instance, an AAA-AGA point mutation results in an arginine-lysine amino acid substitution. Since both these amino acids are positively charged (basic), it is likely that this change in amino acid will have no significant effect on the protein product
  • Missense mutations (also non-synonymous mutations) are base changes that substitute an amino acid for a different amino acid, of different chemical properties. These may or may not be deleterious (harmful) depending on their impact on the protein product
  • Nonsense mutations are base changes that substitute an amino acid-coding codon with a premature stop codon (TGA, TAG or TAA). This leads to premature termination of polypeptide translation and, depending on how prematurely the stop codon is inserted, may be deleterious or neutral in its effect.
Point Mutation

Frame-shift mutations are mutations that involve the removal or addition of one or more base(s), and a subsequent shift in the reading frame of the DNA sequence (i.e. the triplet codons are rearranged). This can be highly deleterious if the mutation occurs early on in the sequence, but even at later intervals may still be harmful.

Frameshift Mutation
Frameshift Mutation

Another way to classify mutations is by their effect on gene function. The broad categories for such mutations are loss-of-function mutation and gain-of-function mutation. These categories may be further divided: for instance, a neomorphic mutation is a gain-of-function mutation that creates an allele with an entirely novel function.

Mutations may also occur at a level above the nucleotide sequence; such mutations alter the structure or number of chromosomes in a cell.

These mutations are called chromosomal aberrations and may include inversions, translocations, deletions and duplications leading either to gene amplification or polyploidisation. As with other mutations, chromosomal aberrations may serve to drive evolution, but often are deleterious to the host organism.

Mutations can be classified in various ways depending on the cause of the mutation, its effect on the function of the gene product or the kind of changes to the structure of the gene itself.

Mutagenic agents such as carcinogens or high-energy radiation lead to changes to the genomic material. Some mutations occur as a natural byproduct of the error rate in DNA or RNA replication mechanisms.

A mutation could be a loss-of-function or gain-of-function mutation, depending on whether the gene product is inactivated or has enhanced activity. In heterozygotes with two copies of every allele, some mutated gene products can suppress the effect of the wild-type allele. These are called dominant negative mutations.

All these effects arise from a change to the structure of a gene or allied chromosomal material. These structural changes can be classified as substitutions, deletions, insertions, amplifications, or translocations.

Substitution Mutations

Substitution mutations are situations where a single nucleotide is changed into another. In organisms having double-stranded DNA or RNA, this usually means that the corresponding base pair is also altered. For example, an A:T base pair could be mutated into a G:C base pair or even a T:A base pair. Depending on the position of this change, it could have a variety of effects.

In highly conserved regions, both in the coding and regulatory stretches of DNA, mutations often lead to deleterious effects. Other, more variable stretches are more accommodating. In the promoter region or in other regulatory parts of the genome, a substitution mutation may change gene expression or the response of the gene to stimulus. Within the coding region, a substitution in the third or wobble position of a codon is called a silent mutation since there is no change to the amino acid sequence. When a substitution mutation results in a new amino acid but with similar properties – it is a neutral or a conserved mutation. For instance, if aspartic acid is substituted with glutamic acid, there is a reasonable chance that there would be very few changes to the biochemistry of the protein.

Lastly, the most drastic substitution mutation is one that results in the premature termination of amino acid elongation because of the sudden appearance of a stop codon in the middle of the coding sequence. For instance, if the UAC codon coding for threonine is mutated into a UAA codon, especially in the 5’ end of the coding sequence, it will likely lead to an extremely short, possibly non-functional protein.

Insertions and Deletions

Insertions and deletions refer to the addition or removal of short stretches of nucleotide sequences. These types of mutations are usually more deleterious than substitutions since they can cause frameshift mutations, altering the entire amino acid sequence downstream of the mutation site. They can lead to a change in polypeptide length, either creating abnormally long proteins that cause aggregates or truncated polypeptides that are non-functional and can clog the translation machinery of the cell.

Insertions and deletions in the regulatory regions of a polypeptide coding sequence or in genes coding for non-coding RNA are less obviously harmful. Here again, the position of the mutation matters – in highly conserved regions, the mutation is more likely to result in negative effects.

Gene Mutation
Gene Mutation

Large-scale mutations

Changes to the nucleotide sequence in genetic material can also occur on a large scale, sometimes involving thousands of base pairs and nucleotides. These kinds of mutations include amplifications, where segments of genetic material are present in multiple copies, and deletions, where a large chunk of genetic material is removed. Occasionally, some parts of the genome are translocated to a different chromosome, or reinserted into the same position, but in an inverted orientation. Translocations and deletions can bring together genes that are normally placed far apart from each other, either leading to the formation of mosaic polypeptides, or to the differential regulation of the genes within the segment.


Mutation may be caused by a wide range of factors. Perhaps the most obvious one is errors in DNA replication. The enzyme DNA polymerase which catalyses the replication of DNA to produce new cells has an error rate of approximately 1 in every 10 million bases. In the human genome (with a haploid genome of 3,000 million bases) this equates to 300 mistakes made per new cell synthesised (note however that DNA polymerase has an error-checking ability so this figure is drastically reduced in practice). Nonetheless, random errors in DNA replication may result in mutagenesis and mutant daughter cells. Errors in DNA replication occur because the organism has to trade-off speed with accuracy. Trying to say the following tongue-twister, with a time limit, may help to illustrate this point:

“I’m not the pheasant plucker, 

I’m the pheasant plucker’s mate

and I’m only plucking pheasants 

‘cause the pheasant plucker’s late

Other biological causes of mutation may include the action of transposons, retrotransposons or certain viruses.

Physical agents which may lead to mutation include X-rays and ionizing radiation, as caused by gamma and ultraviolet (UV) rays. X-rays can break the phosphodiester bonds that constitute the sugar-phosphate backbone of DNA, resulting in deletions or recombinations. Meanwhile, gamma and UV rays may cause dimerisation of adjacent pyrimidines – in particular, ultraviolet radiation results in the formation of thymine dimers.

Physical Mutagens
Physical Mutagens

Chemical modifications of bases may lead to mutation. For instance, deamination of cytosine residues results in the formation of uracil. Because uracil is not usually found in DNA, this is usually quickly corrected. However, in eukaryotes especially, cytosine residues are often methylated. Methylated cytosine residues are deaminated to produce thymine. These mutations are less well-noticed by the proofreading mechanisms since thymine is a common component of DNA, and often a CG pairing will be replaced by a TA pairing as the result of deamination. Depurination is another chemical process, this time involving the removal of purine bases. Once a purine base is removed, it can be replaced by any base randomly chosen by the proofreading mechanism. This means that there is a 1 in 4 chance that there will be no consequence, but a 3 in 4 chance of mutation.

Examples of Mutation

Sickle Cell Disease and Malaria

Sickle cell disease (SCD), so-named due to its characteristic sickling effect on red blood cells, usually manifests via blood clots, anaemia, and bouts of pain known as “sickle-cell crises.” While many of these symptoms can be treated with medication, they still significantly lower the quality of life of their carriers.

Although considered rare and a mutation, SCD is relatively well-researched. It takes place on the 11th chromosome and is catalyzed by the inheritance of an abnormal haemoglobin gene from both parents. As far as global prevalence goes, SCD is the most prevalent among West African populations, with an incidence rate of about 4.0%

Research suggests that the prevalence of SCD in West Africa is not a chance phenomenon. Despite its effects on health, SCD has also been shown to reduce risk of contracting malaria from mosquitoes. As West Africa’s climate allows malaria to thrive, SCD serves as a means of protecting the population.

In all, SCD serves as an example of genetic mutation benefiting the populations it effects. This, in part, is why some genetic mutations endure for decades and even centuries.

Klinefelter’s Calicos

Klinefelter syndrome, also known as XXY syndrome, is a genetic mutation in which a male subject carries an extra X chromosome, therefore carrying the female genotype XX in addition to the traditional male genotype XY. Likewise, males with Klinefelter syndrome often have feminine features, such as breast tissue, and may not be able to reproduce.

As it lies in the genetic code, which is homologous between most species, Klinefelter syndrome is not exclusive to humans. Therefore, cats, dogs, and even whales can inherit XXY genotype.

In cats, the X chromosome carries more than sex-related information. Fur colour, for instance, is carried on the X chromosome.

Furthermore, fur colour is codominant. As male cats typically inherit only one X chromosome and female cats inherit two X chromosomes, female cats are more likely to have multicoloured fur patterns than male cats.

This is especially true for the calico, a cat known for its striking orange-and-black fur. The gene for black fur cannot be carried on the same X chromosome as the gene for orange fur, which makes calico cats almost exclusively female.

However, this does not make the existence of a male calico impossible. Male cats with two X-chromosomes, or genotype XXY, may very well carry the gene for orange fur on one X-chromosome and the gene for black fur, on the other. In this way, they are indeed “Klienfelter’s Calicos.”

Lactose Tolerance

We mentioned earlier how SCD, a mutation marked by sometimes life-threatening physical symptoms, also works to prevent malaria in West Africa. Lactose tolerance is another mutation that benefits those who have it.

Human bodies were originally unable to produce lactase, an enzyme that digests the proteins in cow’s milk, after the first months of life. This is because humans often did not consume milk – or other dairy products, for that matter – into adulthood.

The rise of pasteurization, as well as commercial farming, nearly did away with this old habit. As we can see today, humans of all ages eat cheese and drink milk. Of course, this comes after a significant bodily change. A mutation that prolongs lactase production in humans, which is currently more prevalent in Western nations, allows humans to eat dairy products without stomach pain or nausea.

Like SCD, this mutation remains because it helps humans consume vital nutrients, like calcium and potassium, through a more diverse range of sources.

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