8 Gene Mutations

• Gene mutations arise as a result of a change in the sequence of nucleotides in the DNA of a gene
• Repair mechanisms can correct errors in eukaryotes, but in some cases, cells could still end up with mutations
• Outcome of gene mutations

  A change in the sequence of nucleotides in DNA leads to a change in the sequence of codons in mRNA, which can result in a change in sequence of amino acids in the resulting polypeptide chain. This could then change the 3D conformation of the protein, affecting its function, and subsequently affecting the characteristics (phenotype) of the organism. Thus, genetic mutations can manifest as a disease in the organism
• Types of gene mutations

  1. Substitution

  2. Insertion and Deletion

  3. Inversion
• Gene mutations can result in diseases, including sickle cell anaemia
• Causes of gene mutations

  • Spontaneous errors in DNA replication or spontaneous damage to DNA
  • Exposure to mutagens such as ionising radiation, carcinogens, and some viruses
• Gene mutations and chromosomal aberrations occur in cells during DNA replication and cell division
• Gene mutations can result in inheritable diseases

  Germline mutations occur in the gametes (sex cells) or germ cells of the gonads, while somatic mutations occur in somatic cells of the body and would not be passed on to offspring
• Mutations could manifest in the phenotypes of organisms and lead to diseases
• Substitution mutation

  Occurs when one or more nucleotides (or base pairs) is/are replaced by another nucleotide (or base pair)
• Germline mutations occur in the gametes (sex cells) or germ cells of the gonads


  Can be passed on to offspring
• Point mutation


  Change in just a single base
• Gene mutations


  Involve a change in one or more bases
• Non-conservative missense mutation occurs when the 'new' amino acid has different chemical properties to the original amino acid
• Silent mutation occurs when there is no change in the amino acid being coded for despite a change in the base sequence
• Missense mutation occurs when the change in base sequence within a gene results in a change in the amino acid being coded for
• Point mutations may be the most common type of gene mutation, but changes in two or more bases within the base sequence of the gene can occur as well
• Types of gene mutations

  • Substitution
  • Insertion / addition
  • Deletion
  • Inversion
• Somatic mutations occur in somatic cells of the body


  Not passed on to offspring
• Substitution mutation

  • Thymine replaced by cytosine in the 3’ to 5’ strand, adenine replaced with guanine in the complementary 5’ to 3’ strand
• Conservative missense mutation occurs when the 'new' amino acid has similar chemical properties to the original amino acid
• Nonsense mutation results in the introduction of a stop codon in the mRNA strand, leading to premature termination of translation
• Base substitution may lead to silent mutation if it occurs in the intron (non-coding sequence) of the gene that is transcribed to form intron of the pre-mRNA
• Inversion mutations


  Occur when a segment of nucleotide sequence separates from the allele and re-joins at the original position but it is inverted and the sequence is now reversed: 5’ TATGGCCAA 3’
• Insertion/addition mutation


  Occurs when one or more nucleotides are inserted/added into a gene sequence
• Change in shape of the red blood cell due to the point mutation in sickle cell anaemia
• Change in sequence of amino acids in polypeptide chain due to the point mutation in sickle cell anaemia
• Normal adult haemoglobin (HbA)

  • Globular protein, roughly spherical in shape
  • Quaternary structure of 4 polypeptide chains: 2 α-globin & 2 β-globin
  • One prosthetic haem group attached to each globin chain
• Frameshift mutations

  • Possible results of frameshift mutations: 3’ ATGGCCA 5’
• Sickle Cell Anaemia is caused by a single nucleotide substitution mutation in the gene which codes for the β-globin chain
• The α-globin and β-globin polypeptide chains are coded for by two different genes found on different chromosomes. This means that a mutation in one globin gene is unlikely to affect the other
• Mutation in intron of the gene


  Transcribed to form intron of the pre-mRNA. As intron is removed during mRNA splicing and the mature mRNA formed is not affected by the mutation, the corresponding amino acid sequence is also not affected
• Effects of sickle cell anaemia include: Sickle red blood cells are more fragile causing them to break more easily. They are also actively destroyed in the spleen. This results in the shortage of red blood cells and poor oxygen transport. Possible consequences include: Anaemia, breathlessness, physical weakness, heart failure, weakness, lack of energy
• Change in properties of sickle cell haemoglobin (HbS) due to the point mutation
• The cystic fibrosis transmembrane conductance regulator (CFTR) is involved in cystic fibrosis
• Blood cells are actively destroyed in the spleen, resulting in a shortage of red blood cells and poor oxygen transport
• Keywords

  • Substitution
  • Addition/insertion
  • Deletion
  • Inversion
  • Point mutation
  • Silent mutation
  • Missense mutation
  • Frameshift mutation
  • Sickle cell anaemia
  • Normal adult haemoglobin (HbA)
  • Sickle cell haemoglobin (HbS)
  • Valine
  • Glutamate
  • Cystic fibrosis
  • Cystic fibrosis transmembrane conductance regulator (CFTR)
• Sickle-shaped red blood cells are less flexible than normal red blood cells and may get lodged in small blood vessels, interfering with blood circulation
• Blood cells are more fragile causing them to break more easily
• Possible consequences of fragile blood cells

  • Anaemia, breathlessness, and physical weakness
  • Heart failure
  • Weakness, lack of energy