Gene mutations

Gene mutations are changes in the base sequence of an organism's DNA. They are fundamental to genetic variation and can have various effects on the polypeptide (protein) produced.

• Definition

  • A gene mutation is a random change in the base sequence (structure) of DNA.

  • It involves a change in the DNA base sequence of chromosomes.

  • They are also described as unpredictable changes in the genetic material of an organism.

• Causes of Gene Mutations

  • Gene mutations can arise spontaneously during DNA replication. This occurs when mistakes are made, for instance, a "wrong" base might slot into position during the building of the new strand. DNA polymerase usually "proofreads" and corrects most errors, but some persist.

  • The rate of gene mutation can be increased by mutagenic agents.

• Mutagenic Agents

  • These are substances or environmental factors that increase the rate or probability of mutations occurring.

  • Examples include:

    • Ultraviolet (UV) radiation. It can cause adjacent thymine bases to pair together or modify nitrogenous bases.

    • Ionising radiation (e.g., X-rays, gamma rays, alpha particles, beta particles). These can cause breakage of the DNA molecule.

    • Some chemicals (e.g., base analogs, alkylating agents like mustard gas, benzene, tar in cigarette smoke). These can modify the chemistry of base pairs or bind to DNA, separating strands.

    • Some viruses.

• Types of Gene Mutations

  • Gene mutations involve a change in the base sequence of DNA. The types of errors that can occur include:

    • Substitution: One base is swapped for another (e.g., ATGCCT becomes ATTCCT).

    • Deletion: One or more bases are removed (e.g., ATGCCT becomes ATCCT).

    • Addition (or Insertion): One or more bases are added (e.g., ATGCCT becomes ATGACCT).

    • Duplication: One or more bases are repeated (e.g., ATGCCT becomes ATGCCCCT).

    • Inversion: A sequence of bases is reversed (e.g., ATGCCT becomes ATCCGT).

    • Translocation: A sequence of bases is moved from one location in the genome to another, possibly to a different chromosome.

• Effects on Polypeptides and Protein Structure

  • The order of DNA bases in a gene determines the order of amino acids in a particular polypeptide. Therefore, if a mutation occurs, the sequence of amino acids coded for could be altered.

  • A change in the amino acid sequence (primary structure) can affect how the polypeptide folds up, thereby changing the tertiary structure of the protein, which can then affect its function.

  • Frameshift mutations (additions, deletions, duplications) typically have a huge effect because they change the number of bases, causing a shift in all subsequent base triplets (codons). This means all amino acids from that point onwards will likely be incorrect, resulting in a non-functioning protein or a premature stop codon.

  • Substitution mutations may have less serious effects.

    • Degenerate nature of the genetic code: Because most amino acids are coded for by more than one DNA triplet/codon, a substitution might still code for the same amino acid (a "silent mutation"), resulting in no change to the protein.

    • Even if a different amino acid is coded for, if it has similar properties or is not in a critical region (like an enzyme's active site), the protein's function may remain unchanged.

    • However, a substitution can still introduce a premature stop codon ("nonsense mutation"), leading to an incomplete and non-functional protein. It can also alter a single amino acid, which if critical (e.g., in an active site), can be very detrimental ("missense mutation").

• Hereditary vs. Acquired Mutations

  • Acquired mutations occur in individual cells after fertilization (e.g., in adulthood). If these occur in genes controlling cell division, they can lead to uncontrolled cell division and form tumors/cancers.

  • Hereditary mutations are present in gametes (sex cells) and are passed on to offspring, affecting every cell of the new organism. Some genetic disorders and cancers can be hereditary.

• Link to Diseases and Genetic Disorders

  • Mutations in genes that control cell division (tumour suppressor genes and proto-oncogenes) can lead to cancer.

  • Many genetic disorders are caused by mutations.

    • Sickle cell anemia is a classic example of a base substitution mutation, where one base change (A to T) in the HBB gene leads to a single amino acid change (glutamic acid to valine) in haemoglobin, causing red blood cells to become sickle-shaped under low oxygen conditions.

    • Cystic fibrosis can be caused by various mutations, including nonsense mutations, affecting the CFTR protein.

    • Albinism results from mutations in the TYR gene, often affecting the enzyme tyrosinase, leading to a lack of melanin production.

    • Haemophilia results from mutations in genes coding for clotting factors (e.g., F8 gene) and is sex-linked.

    • Huntington's disease is caused by a dominant allele with a repeated triplet of nucleotides (CAG repeats) in the HTT gene.