DNA mutation lec 2

DNA Mutation and Repair

Lecture Overview

• Instructor: Dr. Andrew Thomas

• Focus on:

  • Molecular consequences of different mutations

  • Frameshift mutations

  • Consequences of oxidative damage to DNA

Types of Mutations

Base Pairing Errors

• Mismatch base pairing from base tautomeric shifts leads to:

  1. Transition mutations:

     • Purine to purine (e.g., G to A)

     • Pyrimidine to pyrimidine (e.g., C to T)

  2. Transversion mutations:

     • Pyrimidine to purine (e.g., T to G) or vice versa

• Transversion mutations are rarer, often involving purine mispairing.

Molecular Consequences of DNA Mutation

• Mutations categorized as:

  • Transitions

  • Transversions

  • Importance of genetic code understanding:

    • Codons: 3 bases code for 1 amino acid or stop signal

    • Code is degenerate (multiple codons can code for the same amino acid)

    • Questions on codon counts, stop/start codons, and transcription enzyme differences.

RNA Transcription

• DNA Sequence:

  • 5’TCG AAT TCT TGA 3’ (DNA)

  • 3’AGC TTA AGA ACT 5’ (template strand)

• RNA Sequence:

  • 5’UCG AAU UCU UGA 3’ (mRNA)

• Amino Acid Sequence:

  • Serine – Asparagine – Serine - Stop

Types of Substitutions

• Substitution Consequences:

  1. Synonymous (silent):

     • No amino acid change (e.g., AGG to CGG, both coding for Arg)

  2. Non-synonymous - causes amino acid change:

     • Missense (conservative): Equivalent amino acid (AAA to AGA, Lys to Arg)

     • Missense (radical): New amino acid coded (AAA to GAA, Lys to Glutamate, significant consequence)

     • Nonsense: New termination codon (CAG to UAG, Glutamine to stop codon, significant consequence)

Frameshift Mutations

• Caused by 1 or 2 bp insertion or deletion, altering the reading frame:

  • Example: THE FAT CAT ATE THE BIG RAT

    • 1 bp deletion: THE FAT ATA TET HEB IGR AT

    • 1 bp insertion: THE FAT CCA TAT ETH EBI GRA T

• Mechanism: New strand loops out during DNA synthesis, common in repetitive DNA sequences (example: CGGGGGGGGTCG)

Larger Deletions and Duplications

• Occur with greater slippage in long repeated sequences:

  • Trinucleotide repeats can lead to such mutations.

  • Recombination between similar sequences on different strands.

Oxidative DNA Damage

• Caused by active oxygen species:

  • Superoxide radicals (O2*), hydrogen peroxide (H2O2), hydroxyl radicals (OH*)

• Sources: By-products of aerobic respiration

• Example of oxidative damage:

  • Guanine to 8-oxo-7-hydrodeoxyguanosine (GO), can mispair with adenine, leading to G replaced by T (transversion).