(5) BIO BOOK 2: Gene and Chromosomal Mutations

Mutations

How Mutations come about:

• Occasionally:

  • Occasional genetic changes enhance the long-term survival of a species

• Most of the time:

  • The survival of an individual demands a high degree of genetic stability.

• Rarely:

  • Cell’s DNA-maintenance processes fail, resulting in a permanent change in DNA

  • Such a change is called a mutation

Mutation:

• It is an alteration to an organism’s characteristics that is inherited, due to a change in the genetic material of a cell, and it can destroy an organism if it occurs in a vital position in the DNA sequence.

• Mutations can involve:

  • Just a single or a few nucleotide pair(s) OR

  • Large regions of a chromosome

Types of Mutations:

• Germline mutation

  • Mutation occurs in germline cells (consisting of germ cells and gametes).

  • It may be transmitted to the offspring and to successive generations

  • If the mutation has an adverse effect on the phenotype of an organism, the mutant condition is referred to as a genetic disorder, or hereditary disease.

• Somatic mutation

  • Mutation occurs in somatic cells

  • These mutations are not inherited by the progeny and hence not passed on to the next generation

Gene / Point Mutations

Gene Mutations:

• They involve chemical changes that affect the DNA sequence of just one gene.

• They involve changes at specific sites in a gene, resulting in a change in one or a few bases in the DNA sequence

Two basic types of changes to a gene can occur:

• Nucleotide Substitutions:

  • The replacement of one nucleotide pair with another

  • This results in one of the following:

    • Missense mutation → A nucleotide substitution in a DNA sequence results in the translation of a different amino acid

    • Nonsense mutation → A nucleotide substitution in a DNA sequence results in a codon for an amino acid being changed into a stop codon, leading to the premature termination of translation

    • Silent mutation → A nucleotide substitution in a DNA sequence changes the mRNA codon. However, the same amino acid is inserted into the protein because of the degeneracy of the genetic code

    • Neutral mutation → A nucleotide substitution in a DNA sequence changes the mRNA codon and amino acid translated. However the resulting amino acid substitution produces no detectable change in the function of the protein translated

• Nucleotide Insertions or Deletions:

  • It is the addition or deletion of one or more nucleotide pair

  • Depending on the location in the DNA sequence and the number of nucleotide pairs added or deleted, one of the following will ensue:

    • Addition or deletion of deoxynucleotides in multiples of 3, which results in (either or):

      • Missense mutation → mRNA codon was added or deleted and the resulting polypeptide has an amino acid added or deleted respectively.

      • Nonsense mutation → A stop codon was added, leading to premature termination of translation.

    • Addition or deletion of deoxynucleotides not in multiples of 3, which results in (either or):

      • Frameshift mutation → mRNA codons subsequent to the insertion or deletion site are changed, resulting in

      • Extensive missense mutation → The subsequent amino acid sequence of the polypeptide is changed.

      • Nonsense mutation → A codon for an amino acid is changed to a stop codon, resulting in a truncated protein.

Gene / Point Mutations — Effects of Nucleotide Substitutions

• Missense Mutation:

  • A nucleotide substitution in a DNA sequence changes the mRNA codon.

  • This results in the translation of a different amino acid

  • The amino acid sequence of the polypeptide is changed, resulting in a change in the specific 3-dimensional conformation of the protein

  • Hence, the function of the protein is altered

  • E.g. Sickle cell anaemia

• Nonsense Mutation:

  • A nucleotide substitution in a DNA sequence changes a codon for an amino acid into a stop codon

  • This results in premature termination of translation.

  • The resulting polypeptide will be shorter (i.e. truncated) than the normal polypeptide encoded

  • The amino acid sequence of the polypeptide is shortened, resulting in a change in the specific three-dimensional conformation of the protein.

  • Hence, the function of the protein is altered

  • Nearly all nonsense mutations result in non-functional proteins.

• Silent Mutation:

  • A nucleotide substitution in a DNA sequence changes the mRNA codon. However, the same amino acid is inserted into the polypeptide because of the degeneracy of the genetic code

  • The amino acid sequence of the polypeptide is unchanged, resulting in no change in the specific three-dimensional conformation of the protein.

  • Hence, the function of the protein is not altered

• Neutral Mutation:

  • A nucleotide substitution in a DNA sequence changes the mRNA codon. However the resulting amino acid produces no detectable change in the function of the protein translated.

  • This could arise from:

    • The substitution of the original amino acid with an amino acid of similar physical and chemical properties OR

    • The substitution of an amino acid residue that is non-essential to that protein’s structure and function

  • The amino acid sequence of the polypeptide is changed, but there is no change in the overall three-dimensional conformation of the protein

  • Hence, the function of the protein is not altered.

Gene / Point Mutations — Effects of Nucleotide Insertions or Deletions

Nucleotide Insertions or Deletions:

• Nucleotide insertions or deletions are additions or losses, respectively, of one or more nucleotide pairs in a gene.

Effects:

• This often has deleterious (harmful) effects.

• Insertions or Deletions NOT in multiple of 3s:

  • As the resulting mRNA is read as a series of non-overlapping codons, an insertion or deletion of nucleotides not in multiples of threes will result in a frameshift mutation.

  • All the nucleotides downstream of the insertion / deletion site will be improperly grouped into codons, resulting in extensive missense mutation

  • The frameshift may also cause a new, premature stop codon to be generated (nonsense mutation) in the reading frame, or result in a read-through of the normal stop codon, resulting in polypeptides of altered lengths.

  • In any case, a frameshift usually results in a non-functional protein

• Insertions or Deletions IN multiple of 3s:

  • This does not lead to a frameshift.

  • The amino acid sequence of the polypeptide chain contains an additional or fewer amino acid(s).

  • This may lead to missense mutation or nonsense mutation

  • The three-dimensional conformation of the protein may be changed hence leading to a change in the function of the protein.

Case Study — Sickle-Cell Anaemia

Sickle-cell anaemia involves a mutation in the -globin gene, which encodes one of the polypeptide subunits that make up haemoglobin (Hb).

Genetic and molecular basis:

• Substitution of a thymine for an adenine at one position in the Hb gene (template strand), which results in a missense mutation (Fig. 7).

• Sixth amino acid residue in polypeptide is changed from a glutamate (hydrophilic) to a valine (hydrophobic).

Specific three-dimensional conformation and function of the Hb protein is altered.

• This substitution creates a hydrophobic spot on the outside of the Hb protein that sticks to the hydrophobic region of an adjacent Hb protein's beta chain.

• The mutant Hb subunits tend to stick to one another when the oxygen concentration is low, particularly when the red blood cells are in capillaries and veins (Fig. 8c).

• The aggregated proteins form fibre-like structures within red blood cells.

• At high oxygen concentration, haemoglobin resumes globular haemoglobin structure.

Physiological effects:

• The fibre-like structures cause the red blood cells to lose their normal morphology and become sickle-shaped. Sickled cells are less able to move through capillaries and can block blood flow, resulting in severe pain and cell death of the surrounding tissue due to shortage in oxygen.

• The sickled red blood cells are also fragile and easily destroyed, further decreasing the oxygen carrying capacity of blood.