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
               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 bonds with "other" pyrimidine
               modified pyrimidine bonds with "other" 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]

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

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

     deamination - conversion of amino  keto group
           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
                       common form of damage in 'ancient' DNA
            replacement of base may produce transversion
            apyrimidinic sites are similar: loss of C or T

     intercalation - base analogue "slips into" DNA helix
            acridine dyes resemble 3-ring base pair
            intercalated analogue read as 'extra' base:
           DNAPol "stutters"  frameshift mutations
                     ethidium bromide formerly used as an intercalating dye of DNA

     Huntington Disease  (OMIM citation 143100)
            Neuro-muscular degeneration, 'choreic' movements, typically 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-reproductive age
              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