6 - DNA Damage + Mutation

• DNA damage is defined as a change to the regular chemical structure of the DNA double helix
• Examples of DNA damage:

  • A break in the phosphodiester backbone of the polynucleotide chain
  • Loss of a base from the deoxyribose sugar
  • Alteration to the chemical structure of a base
  • Mismatched (non-complementary) bases in the double helix
• If DNA damage is replicated then it often leads to mutation
• A mutation is defined as a permanent heritable change in the sequence of an organism's genome
• Point mutations involve alteration, insertion or deletion of one or a few bases at a time
• Chromosome mutations involve rearrangement (translocation), deletion or insertion
• Types of point mutation:

  • Transition mutation (purine to purine/pyramidine to pyramidine, simplest mutation at DNA level)
  • Transversion mutation (purine to pyramidine/pyramidine to purine)
  • Missense mutation (leads to amino acid substitution)
  • Nonsense mutation (changes a codon to a STOP codon leading to premature termination of translation when being transcribed into mRNA)
• More types of point mutation:

  • Neutral mutation (change into an amino acid with similar chemical properties)
  • Silent mutation (changes codon but leads to same amino acid, usually at 3rd position of codon- no effect on encoded protein)
  • Frameshift mutation (addition/deletion of a few bases causing a change in downstream reading frame, tending to have the greatest effect on proteins)
• Ways to classify mutations:

  • Forward mutations (wild type "active" to mutant "defective")
  • Reverse mutations (mutant "defective" to wild type "active")
  • Suppressor mutations (changes sequence at a different location from original mutation in a way that compensates for the original mutation)
• A partial reversion mutation changes the sequence at the site of the original mutation do a different amino acid that fully/partially restores protein function
• A true reversion mutation restores the sequence to code for the wild type amino acid in the affected protein
• Most mutations are spontaneous (arise without exposure to exogenous agents)
• Suppressor mutations can be intragenic (in the same gene) or intergenic (found in different gene- often where proteins interact in complexes)
• Suppressor mutations can be intragenic (in the same gene) or intergenic (different gene- found where proteins interact in complexes)
• Mutations are more common in repetitive sequences
• Mutation rate is higher in somatic cells than in germ line tissues because somatic cells are constantly dividing
• ~30 new mutattions in a 3 Gbp haploid genome are inherited from each parent
• In prokaryotes, there is 1 mutation for every 1 million cell divisions