Introduction to Repeat Expansions

  • Definition: Repeat expansions refer to the abnormal increase in the number of tandem nucleotide repeats in specific regions of the genome.
    • Examples: CAG, CGG, CTG, GAA repeats.

    Key Concepts

    1. Mechanism of Repeat Expansion

      • Replication Slippage:
        • DNA polymerase dissociates temporarily, leading to misalignment and addition of extra repeats.
      • Mismatch Repair Defects:
        • Errors during repair of DNA loops in repetitive regions propagate repeats.
      • Recombination Errors:
        • Unequal crossing over during meiosis adds repeats to one allele.

    2. Thresholds for Pathogenicity

      • Premutation: Repeats below pathogenic thresholds but prone to further expansion.
      • Full Mutation: Repeats exceed critical thresholds, impairing gene function.
      • Disease-specific thresholds:
        • Huntington’s disease: >40 CAG repeats.
        • Fragile X syndrome: >200 CGG repeats.

    3. Types of Repeat Expansions

      • Coding Region Repeats:
        • Polyglutamine diseases (e.g., Huntington’s disease) result in toxic protein aggregates.
      • Non-Coding Region Repeats:
        • Disrupt transcription, splicing, or RNA function (e.g., Fragile X, Myotonic Dystrophy).

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