Mutations: Introduction, Types, Causes and Repair Mechanisms

Mutations: Introduction, Types, Causes and Repair Mechanisms

Mutation definition

  • The structural genes in a chromosome carry the information to build polypeptides.
  • During DNA replication and gene expression, errors can occur that change the structure and function of the polypeptide product.
  • Here, we will focus on those errors that might occur during the DNA replication process or result from harmful agents in the environment.


Sources of Genetic Errors During DNA Replication and Gene Expression
The process of DNA replication can introduce errors into the DNA (mutations). In addition, errors made during transcription or translation also can occur in the RNA transcript or protein sequence produced, respectively. Errors in folding of the final polypeptide is another possible outcome.
  • An organism’s genome can be altered through a permanent and heritable change to one or more nucleotide bases.
  • Such mutations usually involve a change in or disruption to a base sequence in the DNA, especially in a gene.
  • The result is the synthesis of a miscoded mRNA and ultimately a change in one or more amino acids found in the polypeptide during translation.
  • The majority of mutations are harmful because they alter some aspect of cellular activity in a negative way.
  • For example, perhaps a mutation causes an enzyme to fold incorrectly, shutting down an important metabolic pathway in a cell.
  • However, as points out, on rare occasions, a mutation can be beneficial and give the organism a novel property, such as an increased potential of causing disease.

Mutations Can Be Spontaneous or Induced

  • Spontaneous mutations are heritable, random changes to the base sequence in the DNA that result from natural phenomena.
  • These changes could result from errors made and not corrected by DNA polymerase during replication or from physical or chemical agents in the environment.
  • It has been estimated that one such mutation can occur for every 106 to 1010 divisions in a bacterial population.
  • A mutant cell arising from a spontaneous mutation usually is masked by the much larger population of normal cells.
  • However, should the environment favor the mutant, it will multiply and emerge as the predominant form. For example, for many decades doctors used penicillin to treat gonorrhea, which is caused by Neisseria gonorrhoeae.
  • Then, in 1976, a penicillin-resistant strain of N. gonorrhoeae emerged.
  • Many investigators suggested that the penicillin-resistant strain had existed in the N. gonorrhoeae population for centuries, but only with heavy penicillin use in the 1970s could the penicillin-resistant strain arise and surpass the penicillin susceptible forms.
  • The majority of our knowledge of mutations has occur from researches involving induced mutations, which are developed by external physical and chemical agents called mutagens.

Physical Mutagens

  • Ultraviolet (UV) light is a physical mutagen whose energy causes adjacent thymine (or cytosine) bases in the DNA to covalently link together forming dimers.
Ultraviolet Light and DNA
(A) When cells are irradiated with ultraviolet (UV) light either naturally or through experiment, the radiations might affect the cell’s DNA. (B) UV light can cause adjacent thymine molecules to covalently pair (red lines) within the DNA strand to form a thymine dimer.
  • If such type of dimers appear in a protein-coding gene, the RNA polymerase can not place the correct bases (A–A) in mRNA molecules where the dimers are situated.
  • In addition, ionizing radiations, such as gamma rays and X-rays, can cause physical breaks in the double-strand DNA. Loss of cellular function usually results.

Chemical Mutagens

  • Many chemicals are mutagenic; that is, they can cause mutations.
  • Nitrous acid is an example of a chemical mutagen that converts DNA’s adenine bases to hypoxanthine bases.

The Effect of Chemical Mutagens

  • Adenine generally base pair with thymine, but the existence of hypoxanthine creates a base pairing with cytosine while replication.
  • After, if replication happens from the gene with the cytosine mutation, the mRNA will have a guanine base insted of an adenine base.
  • Mutations also are induced by base analogs, which bear a close chemical similarity to a normal nucleotide.
  • For example, acyclovir is a base analog that can substitute for guanine during virus replication.
The Effect of Chemical Mutagens1
Base analogs induce mutations by substituting for nitrogenous bases in the synthesis of DNA. Note the similarity in chemical structure between guanosine and the base analog acyclovir.
  • However, incorporation of acyclovir blocks further viral replication because the analog lacks the deoxyribose sugar needed for the addition of the next nucleotide. As a result, new virus particles cannot be produced.
  • Acyclovir, therefore, is an effective treatment to limit infections caused by the herpes simplex 1 and 2 viruses (cold sores and genital herpes), varicella-zoster virus (shingles and chickenpox), and Epstein-Barr virus (mononucleosis).

Point Mutations Can Affect Gene Expression

  • Regardless of the cause of the mutation, one of the most common results is a point mutation, which usually affects just one point (a base pair) in a gene.
  • Such mutations might be a change to or substitution of a different base pair or a deletion or addition of a base.

Base-Pair Substitutions mutation

  • If a point mutation creates a base-pair substitution, the transcription of that gene might have one wrong base in the mRNA sequence of codons.
  • Perhaps one way to see the effects of such changes is using an English sentence made up of three-letter words (representing codons) in which one letter has been changed.
  • As three-letter words, the letter substitution still reads correctly, but the sentence makes less sense.
    • Normal sequence: THE FAT CAT ATE THE RAT
      Substitution (H for C): THE FAT HAT ATE THE RAT
  • If the substitution, because of redundancy in the genetic code, does not alter the amino acid sequence, the change is referred to as a silent mutation because there is no change in protein function.
Results of Point Mutations
(A) The normal sequence of bases in a gene. (B) Base-pair substitutions can produce silent, missense, or nonsense mutations.
  • If a base-pair substitution does result in a wrong amino acid in a polypeptide, the change is referred to as a missense mutation because the polypeptide is still assembled but might not have the correct shape.
  • Our sentence analogy presented above is an example of a missense mutation.
  • Finally, if the substitution causes a codon to become a stop codon, the change is called a nonsense mutation because translation is terminated prematurely, and any polypeptide produced probably will be nonfunctional.

Base-Pair Deletion or Insertion

  • Point mutations also can leads to the loss or addition of a base in a gene, producing in an improper quantity of bases.
  • Again, using our English sentence analogy, we can see how a deletion or insertion of one letter affects the reading frame of the three letter word sentence.
    • Normal sequence: THE FAT CAT ATE THE RAT
      Deletion: THE F_T CAT ATE THE RAT
      Insertion: THE FAT ACA TAT ETH E RAT
  • As you can see, the “sentence mutations” are nonsense when reading the sentence as three-letter words. The same is true in a cell.
  • Ribosomes always read three letters (one codon) at one time, producing potentially extensive issues in the amino acid sequence if there are too few or too many letters.
Base-Pair Deletion or Insertion
Deletions or insertions shift the reading frame of the ribosome.
  • Thus, like our English sentence, the deletion or addition of a base will cause a “reading frameshift” because the ribosome always reads the genetic code in groups of three bases.
  • Therefore, loss or addition of a base also represents a frameshift mutation because it shifts the reading of the code by one base.
  • The result is serious sequence errors in the amino acids, which will probably produce an abnormal protein (nonsense) unable to carry out its functional role in the cell.

Repair Mechanisms Attempt to Correct Mistakes or Damage in the DNA

  • The fact that DNA is double stranded is not an accident.
  • By being double stranded, one polynucleotide strand can act as the master copy or template to repair mismatches between strands or distortions within one strand.
  • Therefore, if the damaged DNA is repaired before the cell divides, no mutation will result.
  • Bacterial cells, such as E. coli, have two repair systems to mend damaged DNA.

Mismatch Repair

  • Realize that during the life of a microbial cell cellular DNA endures thousands of potentially damaging events resulting from DNA replication errors.
  • Even though DNA polymerase is very accurate in proofreading during replication, errors (mismatched nucleotides) are sometimes missed. Mismatch repair can be used to detect and repair these errors.
  • First, mismatch correction enzymes scan newly synthesized DNA for any mismatched pairs.
  • Finding such a pair, the enzymes cut out (excise) a small segment of the polynucleotide strand containing the mismatched nucleotides.
  • A DNA polymerase then uses the old strand as a template to replace the excised nucleotide segment with the correct set of bases, which is sealed in place by a DNA ligase.

Nucleotide Excision Repair

Nucleotide Excision Repair
Thymine dimer distortion triggers photolyase enzymes to repair the damaged DNA
  • Some nucleotide base changes can be caused by physical mutagens that distort the DNA double helix. If such distortions occur, enzymes detect the distortions and carry out nucleotide excision repair.
  • The enzymes remove a short section of the affected DNA strand and repair the damage with the correct nucleotides using DNA polymerase and DNA ligase to reattach the strands.
  • The ability of UV light to cause thymine dimer formation. Such distortions in the double helix are detected and corrected by the enzyme photolyase.
  • The enzyme binds to the dimer and, when exposed to visible light (photoreactivation), the enzyme breaks the bond holding the thymine dimer together.
  • An impressive example of a very robust DNA repair system is seen in Deinococcus radiodurans, the subject of Still, realize that DNA repair is seldom 100% perfect.
  • Sometimes “shoddy repairs” fail to correct an error and the mutation becomes “locked in” and is inheritable, because it now exists as part of the master copy that can be transferred to future generations of cells during cell division.

Reference and Sources


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