What is the biochemical and molecular basis of mutations?

Types of Mutations

Mutations can be broadly classified based on the scale of the change in the DNA sequence:

• Point Mutations: These involve changes in a single nucleotide base.
  • Substitutions: One base is replaced by another. These can be further categorized as:
    • Transitions: Purine replaced by purine (A ↔ G) or pyrimidine replaced by pyrimidine (C ↔ T).
    • Transversions: Purine replaced by pyrimidine or vice versa.
  • Insertions: Addition of one or more nucleotide bases.
  • Deletions: Removal of one or more nucleotide bases.
• Frameshift Mutations: Insertions or deletions that are not multiples of three nucleotides. These alter the reading frame of the gene, leading to a completely different amino acid sequence downstream of the mutation.
• Chromosomal Mutations: Large-scale changes affecting entire chromosomes or significant portions of them. These include:
  • Deletions: Loss of a chromosomal segment.
  • Duplications: Repetition of a chromosomal segment.
  • Inversions: Reversal of a chromosomal segment.
  • Translocations: Transfer of a chromosomal segment to another chromosome.

Biochemical Causes of Mutations

Mutations arise from a variety of biochemical processes:

• Replication Errors: DNA polymerase, while highly accurate, can occasionally incorporate incorrect nucleotides during DNA replication. Proofreading mechanisms reduce this error rate, but some errors persist.
• Spontaneous Chemical Changes:
  • Depurination: Loss of a purine base (A or G) from the DNA backbone.
  • Deamination: Removal of an amino group from a base, e.g., cytosine to uracil.
  • Tautomeric Shifts: Temporary changes in the chemical structure of bases, leading to incorrect base pairing.
• Chemical Mutagens: These are chemicals that directly alter DNA structure.
  • Base Analogs: Chemicals similar to normal bases that can be incorporated into DNA but cause mispairing (e.g., 5-bromouracil).
  • Intercalating Agents: Flat molecules that insert between DNA base pairs, distorting the helix and causing insertions or deletions (e.g., ethidium bromide).
  • DNA-Reactive Chemicals: Chemicals that directly modify bases (e.g., alkylating agents).
• Radiation:
  • UV Radiation: Causes the formation of pyrimidine dimers (e.g., thymine dimers), distorting the DNA helix and blocking replication.
  • Ionizing Radiation (X-rays, Gamma rays): Causes single- and double-strand breaks in DNA, as well as base modifications.

Molecular Consequences of Mutations

The molecular consequences of mutations depend on the type of mutation and its location within the genome:

• Silent Mutations: Base substitutions that do not change the amino acid sequence due to the degeneracy of the genetic code.
• Missense Mutations: Base substitutions that result in a different amino acid being incorporated into the protein. This can alter protein function, ranging from minor effects to complete loss of function.
• Nonsense Mutations: Base substitutions that create a premature stop codon, leading to a truncated and usually non-functional protein.
• Frameshift Mutations: Lead to a completely altered amino acid sequence downstream of the mutation, often resulting in a non-functional protein.
• Chromosomal Mutations: Can lead to gene dosage imbalances, disruption of gene regulation, and altered chromosome structure, often resulting in severe developmental abnormalities or cancer.

The cellular response to mutations involves DNA repair mechanisms, such as mismatch repair, base excision repair, and nucleotide excision repair. However, these mechanisms are not perfect, and some mutations escape repair, leading to genetic variation.

Mutation Type	Biochemical Cause	Molecular Consequence
Point Mutation (Substitution)	Tautomeric shift, chemical mutagen	Silent, Missense, or Nonsense
Frameshift Mutation	Insertion or deletion (not multiple of 3)	Altered amino acid sequence, non-functional protein
Chromosomal Deletion	Double-strand break, non-homologous end joining	Loss of genes, gene dosage imbalance