Genetic Variations and Trinucleotide Repeat Expansion

Genetic Variations

• Genetic variations can be classified into two types: polymorphism (frequency > 1%) and mutation (does not affect the population)
• Mutations can be heritable alterations or changes in genetic material that can be harmful or beneficial

Trinucleotide Repeat Expansion

• Identified as the mutational basis for single gene neurological disorders such as:
  • Fragile X syndrome
  • Huntington's disease
  • Myotonic dystrophy
  • Spinocerebellar ataxia
  • Friedreich ataxia
• Classification:
  • Polyglutamine (or PolyQ) diseases: repeated codon is CAG, which codes for glutamine (Q) resulting in a polyglutamine tract
  • Non-polyglutamine diseases: repeated codons do not code for glutamine

Fragile X Syndrome

• Most common single cause of inherited mental retardation
• Located on the long arm of the X chromosome - "CGG" in the FMR1 gene
• Repeat number and phenotype effect:
  • ≤ 45: unaffected individuals
  • 50 to 199: no adverse effect on phenotype
  • Pre-mutation: over 200
  • Full mutation: fragile X syndrome, silences gene expression and causes the clinical syndrome

Substitutions

• Single base pair substitutions
• Can be synonymous or silent mutations
• Non-synonymous mutations:
  • Mis-sense mutations: alter the encoded protein and result in abnormal function
  • Nonsense mutations: generate a stop codon, resulting in premature termination of translation of the peptide chain

Dynamic or Unstable Mutations

• Triplet repeats: a normal feature in a genome
• Can be unstable and expand, leading to adverse phenotypic effects

Mutations

• Can be heritable alterations or changes in genetic material
• Usually harmful, but can be beneficial in evolution
• Can arise spontaneously through errors in DNA replication and repair
• Examples:
  • Sickle cell disease: a single base substitution (6th codon of the beta-globin gene from GAG to GTG)
  • Cystic fibrosis: over 700 mutations have been described, with ΔF508 accounting for approximately 70% of all cases in northern Europeans
  • Duchenne Muscular Dystrophy (DMD): mutations include deletion, duplication, and point mutations

Insertions, Deletions, and Duplications

• Fixed and stable mutations
• Insertions: addition of one or more nucleotides into a gene, can interrupt the reading frame
• Deletions: loss of one or more nucleotides, can disrupt the reading frame
• Duplications: doubling of the same nucleotides, can cause disorders such as DMD and Charcot-Marie-Tooth disease

Reading Frame

• Important for maintaining the correct sequence of amino acids in a protein

Learn about genetic variations, including polymorphisms and mutations, and their role in single gene neurological disorders such as Fragile X syndrome and Huntington's disease.