Caused by changes in the DNA sequence

  • There are many different categories of mutations
    • gametic or somatic
    • phenotypic effect - recessive, dominant, sexlinked, morphological, nutritional, behavioral, regulatory, lethal, conditional, etc.
    • type of change in the DNA or protein
      • DNA - transition, transversion, deletion, insertion
      • protein - silent, neutral, missense, nonsense, frameshift

Detection of mutations

  • Assay systems in bacteria and fungi - prototrophs and auxotrophs, resistance
  • fruit flies - ClB and attached-X detection systems
  • plants - amino acid composition and tissue culture auxotrophs
  • human - pedigree analysis

Spontaneous Mutations Rates

  • rates are very low (1x10-8 to 1x10-5)
  • rates vary from species to species (lower in prokaryotes)
  • rates vary from gene to gene

Molecular Basis of Mutations

  • replication mistakes
    • hey, so I goof once every 10 million bases. Think you could do any better?
    • 3'-5' exonuclease allows editing
    • tautomerization (keto - enol and amino - imino) causes transition mutations
    • slippage leads to small insertions and deletions (frameshifts)
      • caused by repeated sequences
        • Fragile-X
          • 50 repeats of CGG is normal
          • 50 to 200 is a carrier (anticipation)
          • >200 causes mental retardaton
        • also the cause of Huntington's (CAG) and Myotonic dystrophy (CTG)
    • damage to the DNA template
      • apurinic sites (AP sites) caused by loss of the base (the glycosidic bond breaks)
      • deamination of cytosine to uracil (or adenine to hypoxanthine)
        • usually repaired by uracil-DNA-glycosidase
        • however, 5-methylcytosine becomes thymidine and can't be repaired
          • methylation of cytosine occurs at only specific locations (only CG in mammals)
            • leads to mutational hot spots
            • many fewer CG's than would be expected
      • radiation
        • UV - thymine dimers
        • gamma rays and X rays - generate free radicals
          • can not only change bases but can also break chromosomes
      • Chemical mutagens
        • base analogs
          • 5-bromouracil can pair with A or G
          • 2-aminopurine can pair with T or C
        • modifying agents
          • alkylating agents (add alkyl groups )
            • nitrosoguanidine (NG) attacks N7 of guanine and N3 of adenine
            • ethylmethanesulfonate (EMS) attacks O6 of guanine
          • can cause mispairing unless the damaged base is removed
            • removal of base creates apurinic site (sugar only) -AP polymerase will put a random base opposite AP site
          • Aflatoxin B1 attacks N7 of guanine - AP site
          • Nitrous acid converts NH2 to =O (deamination)
        • intercalating agents
          • insert into the DNA between the stacked bases, this causes insertions and deletions
            • acridine orange
            • proflavin
            • ICR-191
      • transposons

This document is copyright of Jeff Bell
Last Update: Thursday, July 13, 2006