Gene Mutations

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A gene is a part of DNA that codes for the synthesis of one protein. The entire DNA is made up of thousands of genes that directly control all the functions of a cell via protein synthesis. The sequence of nucleotides in a gene determines the sequence of amino acids in a polypeptide. Therefore, the nucleotide sequence should be preserved for normal protein synthesis. Any changes in the nucleotide sequence will result in the synthesis of abnormal proteins. 

Any change in the nucleotide sequence of DNA is called a mutation. The factors that cause mutations are termed as mutagenic or carcinogenic agents. In this article, we will study different types of mutations, their causes, and their effects on the body. We will also briefly study the DNA repair methods that a cell adopts to correct mutations. 

Genetic Code

Before going into the details of mutations, it is important to have some understanding of genetic code. Genetic code can be referred to as a dictionary that recognizes the correspondence between the nucleotide sequence in a gene and the sequence of amino acids in a polypeptide chain. 

Genetic code is composed of three-letter words called codons that are present on the mRNA. 


A codon is a sequence of three nucleotides that codes for one amino acid in the polypeptide chain. Each codon is regarded as one word made up of three letters, that is read without any space. The four nucleotide bases (A, U, G and C) are used to form three-letter combinations. A total of 64 such comb9inations or codons have been formed.

Out of the 64 codons, three of them do not code for any amino acids. These are termed as terminations codons as they terminate the process of protein synthesis. One codon is always present at the beginning of the mRNA chain, called initiation codon. This codon (AUG) codes for methionine amino acid. 

If either one of the base is changed in the codon, a different amino acid becomes incorporated into the polypeptide chain. The polypeptide thus formed is non-functional and undergoes denaturation. 


The following characteristics of genetic code are important;

  • Genetic code is specific as one codon always codes for the same amino acid
  • Although one codon always codes for only one amino acid, one amino acid may be coded by more than one codon because 61 codons code for only 20 amino acids. This property is called the degeneracy of genetic code.
  • It is non-overlapping and comma less. It is always read from one specific starting point without any break. 

Types of Mutations

As we have understood how a gene works and why the position of even one nucleotide is important in the sequence, let us now move our discussion towards types of mutations. 

One thing should be kept in mind that the genetic code is present on mRNA while the mutations always occur in the gene. Once the nucleotide sequence of a gene has been altered, the mRNA transcribed from this gene will also have abnormal nucleotide sequence. 

The following are different types of mutations that have been identified so far. 

Point Mutations

Such mutations result from changes in a single base or nucleotide in the codon. They are also called base substitution mutations. Such mutations  can be of two types; 

  • Transition: In such mutations, a given pyrimidine is changed into another pyrimidine or a given purine is changed into another purine. 
  • Transversion: These mutations are produced when a given pyrimidine is replaced by a purine and vice versa. 

The mRNA made from such a mutated gene will also possess a different base at the specified location. Single base change in the mRNA can produce the following effects. 

  • Silent mutation: If the new codon made after mutation codes for the same amino acid, it has no effect on the protein structure and normal protein is made. Such a mutation is called a silent mutation. It mostly occurs when the third nucleotide in the codon is altered. 
  • Missense mutation: If the new codon resulting from the mutation codes for a different amino acid, a different amino acid is mistakenly incorporated into the protein structure. Such a mutation is called a missense mutation. The mistaken mutation may be acceptable, partly acceptable, or not acceptable at all by the protein depending on its location. 
  • Nonsense mutation: In this case, the mutated codon is a termination codon. It causes early termination of protein synthesis. The premature protein thus formed is discarded by the cell. 


An example of point mutation is sickle cell anemia. In this case, a missense mutation causes replacement of glutamic acid by valine in the beta chains of hemoglobin. The hemoglobin thus formed precipitates in the RBCs, changing their shape from biconcave to crescent-like. Such RBCs are rapidly destroyed as they are unable to squeeze through small capillaries. 

Frameshift Mutations

This type of mutation occurs when one or two nucleotides are deleted or inserted into the DNA. Recall that the genetic code is nonoverlapping and comma less. The mRNA formed from a gene with a deleted or inserted nucleotide has an altered reading frame. The missing base is not recognized by the translation machinery as the genetic code is read without any space or punctuation. 

This results in a massive change in the protein structure past the deleted nucleotide. A termination codon may be generated causing the premature termination of protein synthesis. 

A frameshift mutation occurs only when one or two nucleotides are deleted or inserted into the gene. 

If three or multiple of three nucleotides are deleted from the gene, the resulting protein will have one missing amino acid at the specified location. An example of three-nucleotide deletion is seen in cystic fibrosis. In this case, three nucleotides deletion in the CFTR gene result in abnormal protein, missing phenylalanine amino acid at the 508th position. This abnormal protein is rapidly destroyed by the action of proteasomes. 

Similarly, if three or multiple of three nucleotides are inserted into the gene, the resulting protein will have one additional amino acid at the specified location. 

Splice-site Mutations

The pre-mRNA transcribed from a gene has several non-coding intervening sequences called introns. These introns are removed from pre-mRNA to form a functional mRNA molecule. This process is called splicing and takes place on specific sites called splice-site. 

If a mutation occurs at a splice-site, it affects the way introns are removed. A gene may be silenced by removing it along with the introns due to abnormal splice-site. Such mutations result in proteins with an aberrant structure.  


An example of splice-site mutation is seen in myotonic dystrophy. It is a genetic muscular disorder in which the protein kinase gene is silenced because of mutation at the splice-site. The patient suffers from progressive muscular weakness and loss of muscular function. 

Causes of Mutations

Mutations can be spontaneous or induced. They may also occur during the process of DNA replication. Here are some of the important causes of mutations. 

Spontaneous Mutations

Some mutations can arise spontaneously in any type of cell. Most of such mutations are seen in highly proliferating cells such as cells of the intestines, skin cells, etc. They occur at the frequency of 10-4  to 10-7 per cell in one generation. The following different changes can occur as a result of spontaneous mutations at the molecular level. 

  • Tautomerization, in which the position of a hydrogen atom is changed altering the base pairing due to different pattern of hydrogen bonding.
  •  Depurination, a purine base is lost resulting in an empty site. 
  • Deamination, hydrol7ysis of the amino group changes base from cytosine to uracil and adenine to hypoxanthine.

Such mutations can arise in normal healthy cells with even zero-probability of being affected. 

Mutations during DNA Replication

Despite the most effective proof-reading, some mutations may arise during the process of DNA replication. These include the addition of a nucleotide, mismatched pairing, and deletion of nucleotides. Such mutations are normally removed by the DNA repair system. They only pass to the next generation if the DNA repair mechanism fails.

Induced Mutations

Most of the mutations are caused by external environmental factors. Such factors that damage the DNA and cause mutations are called carcinogens. 

Carcinogens have two major types; chemical carcinogens and radiations.

Chemical Carcinogens

They include five major classes of chemical compounds.

  • Polycyclic aromatic hydrocarbons such as benzopyrene present in cigarettes 
  • Aromatic amine such as 4-acetylaminofluorene
  • Nitrosamines such as diethylnitrosamine and dimethylnitrosamine
  • Drugs like cyclophosphamide and diethylstilbestrol
  • Naturally occurring compounds like aflatoxin made by some fungi

These chemical compounds can cause mutations via different mechanisms. 


The exposure of cells to different types of radiations also cause gene mutations. The most harmful radiations are UV-light and ionized radiations like X-rays. 

They can cause the following types of damage to the DNA.

  • Formation of pyrimidine dimers within the DNA strand
  • Removal of bases from the gene resulting in apurinic or apyrimidinic sites
  • Single or double-strand breaks within the DNA
  • Cross-linking of DNA strands

DNA Repair Mechanisms

Cells have extensive repair mechanisms that can effectively repair any mutation in the genes. The harmful effects of mutations are only seen when the DNA repair mechanisms fail to correct these mutations. 

The following mechanisms are employed by the cells to tackle with the mutations. 

Mismatch Repair

The mutations in which bases are mismatched in the DNA strand are corrected via this mechanism. It involves the use of special proteins called Mut proteins. 

When the mismatch occurs in a daughter DNA strand, the mismatch is recognized by the Mut proteins. They release a segment of daughter DNA containing the mismatch portion. The gap in the strand is then filled by DNA polymerase with the correct base. The ligase enzyme is then used to join the newly synthesized piece of DNA. 

Nucleotide Excision Repair

This mechanism is used to repair the dimers formed by UV rays. The dimers are recognized by a UV specific endonuclease and exonuclease (a single enzyme with two activities). This enzyme creates a kink on both sides of a small segment containing dimer. This segment is then removed from the strand. the gap thus created is filled by the DNA polymerase while DNA ligase is used to join the segments. 

Base Excision Repair

This process removes the abnormal bases present in the gene. The abnormal base is recognized by a specific glycosylase enzyme that hydrolytically cleaves the base from the strand, leaving behind an empty site. 

The empty site is then filled by the action of DNA polymerase and DNA ligase. 

End-Joining Repair

This mechanism is used to remove the strand breaks in DNA. This repair can be carried out in two ways;

  • Non-homologous end-joining; the non-homologous DNA strands are joined. processed and ligated
  • Homologous end-joining; involves the joining of homologous DNA strands


Gene mutations are the damage to the DNA that result in altered nucleotide sequence in the gene. As a result, the amino acid sequence in the proteins is altered and non-functional proteins are made. 

When a mutation occurs in a gene, the mRNA transcribed from this gene also have an altered nucleotide sequence.

If a single base is altered, it is called point mutations. Point mutation can produce three types of affected codon;

  • Silent mutation, if the mutated codon codes for the same amino acid
  • Missense mutation, if the mutated codon codes for a different amino acid
  • Nonsense mutation, if the mutated codon is a stop codon

Frameshift mutation occurs due to the insertion or deletion of one or two nucleotides in the gene. The entire reading frame of the mRNA is shifted and a protein with aberrant structure is made.

If a mutation occurs on splice-site, it can cause gene silencing. This is seen in myotonic dystrophy. 

Different factors can cause gene mutations. 

  • They can spontaneously arise in any cell
  • They can occur during DNA replication
  • They can be caused by external factors called carcinogens, that might be chemicals or radiations

Cells have effective DNA repair mechanisms to remove the mutations. Some of the important methods include;

  • Mismatch repair 
  • Nucleotide excision repair
  • Base excision repair
  • End-joining repair

A mutation is only harmful if it cannot be corrected by the DNA repair mechanisms. 


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