# 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.