203m1a

• Mutation


  A change or variation in the base sequence of DNA
• Change in the base sequence of a gene


  Causes a change in the gene product coded by that gene
• New mutations


  Arise in somatic cells or in the germline
• If a germline mutation does not seriously impair an individual's ability to have children, it can spread
• Variation in DNA sequences occurs rarely as a result of new mutations (de novo mutation)
• Most disease associated mutations are inherited
• Types of mutations


  • Positive
  • Neutral
  • Damaging
  • Lethal
• Endogenous mutations


  Due to spontaneous errors in DNA replication and repair
• Mutations occur about 1/10 million bp, 99.9% will be repaired by proof-reading mechanisms, therefore ~ 1 nucleotide change per cell division
• Mutagens


  Compounds that can increase the occurrence of mutations
• Types of mutations


  • Chromosome disorders
  • Single gene (monogenic) disorders
  • Complex/multifactorial disorders
• Chromosome disorders


  • Due to an excess or deficiency of the genes contained in whole chromosomes or chromosome segments
  • Affect about 7 per 1,000 liveborn infants
  • Account for ~50% of all spontaneous first-trimester miscarriages
• Structural chromosome abnormalities


  • Arise due to errors during cell division when chromosomes align
  • Homologous recombination between areas of concentrated repeated sequences frequently creates deletions and duplications
  • Usually a severe phenotype if multiple genes are involved
  • Duplications and deletions alter gene dosage due to copy number variations
• Single gene disorders


  • Caused by individual mutant genes
  • May be recessive or dominant
  • May be contained in the mitochondrial or nuclear genomes
  • Usually exhibit obvious pedigree patterns
  • Although individually rare, they are responsible for a significant proportion of disease and death
  • ~2% of a population will be affected
• Types of pathogenic mutations

  • Mutations in protein coding region (Exons)
  • Mutations disrupting RNA stability or RNA splicing
  • Mutations affecting gene regulation or dosage
• Frameshift mutations


  Insertion or deletion of a base or bases, resulting in an entirely different sequence of amino acids from the point of insertion or deletion, usually ending in a premature truncation of the protein
• Autosomal recessive disease


  Generally rare, where the remaining non-mutated copy of the gene creates enough 'good' protein to compensate
• The most common autosomal recessive disease is cystic fibrosis in Caucasian children where 1:2,000 has CF, with a carrier frequency of 1:30
• A mutation can be a single base or multiple bases, gained or lost from the genome in any cell in the body
• A 'disease-associated mutation' can be of a single gene or multiple genes
• The mutation can be present on the autosomes or sex chromosomes
• A mutation can have dominant or recessive action on phenotype
• If a mutation occurs in the germline it can be inherited by offspring
• Inheritance of mutations can be complex and inheritance patterns are disease specific