non-heritable (but gene-based)                            

 Nucleotide interchanges are of two types
        transitions   - alternative pyrimidines [ CT ]  or purines [ AG ]
        transversions -  purine  pyrimidine [C / T A / G]
        Most mutations are transitions: interchanges of bases of same shape

Spontaneous mutation
       tautomeric shift - spontaneous, transient rearrangement to alternative form [IG1 16.07]
               keto (standard)  enol  (rare) forms of G & T
               amino (standard)  imino (rare) forms of A & C

       Non-standard bases have altered pairing rules :
               modified purine pairs with "wrong" pyrimidine
               modified pyrimidine pairs with "wrong" purine

        T' (enol)     pairs with G (keto)
        C' (imino)  pairs with A (amino)
        G' (enol)    pairs with T (keto)
        A' (imino)  pairs with C (amino)

        A tautomeric shift produces a transition mutation in the complementary strand [see example] [cf IG1 16.12]:

Homework: Based on this diagram, show that tautomeric shifts of the C, G, & T bases also produce transition mutations

Induced mutation - chemical modification of DNA alters base pairing [Table16.01]

    alkylation - addition of alkyl group (methyl CH₃- or ethyl CH₃-CH₂-)
          ethyl methane sulfonate (EMS) is a common laboratory mutagen
       G  6-ethyl G , pairs with T

     deamination - conversion of amino  keto group [IG1 16.13]
           nitrous acid (HNO₂) is a common food additive / preservative
       C  U by loss of NH_2, pairs with A
       A hypoxanthine by loss of NH₂, pairs with C

     depurination - loss of purine (A or G) base in intact polynucleotide
            produces an apurinic  site
                       a common form of damage in 'ancient' DNA  [IG1 16.16]
            replacement of base may produce transversion
            apyrimidinic sites are similar: loss of C or T

     intercalation - base analogue "slips into" DNA helix [IG1 16.14]
            acridine dyes resemble 3-ring base pair
            intercalated analogue read as 'extra' base:
           DNAPol "stutters"  frameshift mutations
                     ethidium bromide is a fluorescent intercalating dye of DNA

     Huntington Disease  (OMIM citation 143100)
            Neuro-muscular degeneration, 'choreic' movements, typically with late onset

            Huntingtin [sic] (HTT) locus has (CAG)_n repeat near 5' end [4p16.3]
                 # copies in affected individuals inversely correlated with severity & age of onset
                        9 ~ 36      unaffected,
                      36 ~ 41     incomplete penetrance
                            >41      adult onset
                            >50      juvenile onset

            Huntingtin Protein with poly-glutamine (Gln)_n repeat has been isolated  [IG1 16.10]
                 autosomal dominant inheritance:
                      phenotype is a consequence of presence of modified protein:
                      high copy HD alleles 'dominate' low-copy standard alleles

         A genetic counseling ethical dilemma:
              Symptoms typically appear post-reproductively
              Tiresias' Dilemma: 'It is but sorrow to be wise when wisdom profits not.'

  Fragile-X Syndrome [Martin-Bell Syndrome] (OMIM citation 300624)
            Most common form of inherited predisposition to mental retardation
            (CGG)_n repeat occurs upstream from 5' end of FMR-1 gene [Xq28]
                      6 ~   54     unaffected,
                    55 ~ 200    X-linked female carriers, unaffected
                         > 200     affected sons