Sites where all possible substitutions are synonymous are also known as 'four-fold degenerate' sites and are relatively common in frequency compared to other coding changes such that their frequency is similar to substitution rates within introns. 'Two-fold degenerate' sites refer to positions where one of three potential base substitutions is synonymous. Non-degenerate, four-fold degenerate, and two-fold degenerate sites make up
65%, 16%, and 19% respectively of the base positions in human codons. The nature of the genetic code promotes conservative missense substitutions as the sequence of codons specifying similar amino acids are themselves similar (for example aspara-gine (GAU, GAC) and glutamic acid (GAA, GAG)). The 'mutability' of specific amino acids is seen to vary, from highly mutable (for example threonine) to rarely mutated (cysteine).
(B) Conservative missense mutation
Window Position Human Mar. 2006 chr11:S,204,770-S,204,830 (61 bp) X
chrll: I 5204775 I 5204780 I 5204785 I 5204790 I 5204795 I 5204800 I 5204805 I 5204810 | 5204815 I T 5204825 I
Normal <--- A ¡g T g !g a a ;c g g !g g t ¡g t c !c c g ¡t c a ¡t T G ! C C g ¡t c t !g a a ¡g a g ;g a g !t c c !t c a ¡g t c ¡t a c !g t g !g T a !c CA
a ¡G t G !g a a !c g g !g g t ¡g t c !c c g !t c a !t t g ! C C G !t c t !g a a !g a g !g a g !t c c !t c a !g t c !t |_j c ¡g t g !g t a !c c a
Variant results in His to Leu ^ amino acid substitution l
(C) Nonsense mutation
w Position X Human Mar. 2006 chr11:5,204,770-5,204,830 (61 bp)
chr11: I 5204775 t 5204780 I 5204785 I 5204790 I 5204795 I 5204800 I 5204805 I 5204810 I 5204815 I 5204820 I 5204825 I <--- a!g t g !g a fAl c g g !g g t!g t c ! C C G ! T C a!t t g ! C C G !t c t!g a a!g A G !G A G ! T C C ! T ca!g T C !t a c!g t g!g t a!c C A
Substitution results in UAG nonsense codon
(D) Frameshift due to nucleotide deletion ________k v ' HBB:c.20delA
Window Position Human Mar. 2006 chr11:5,204,770-5,204,830 (61 bp) I
chr11: I 5204775 I 5204780 I 5204785 I 5204790 I 5204795 I 5204800 I 5204805 I T I 5204815 I 5204820 I 5204825 I Normal <--- a!g t g;g a a;c g g;g g t;g t c ! c c g ! t c a;t t g ! c c g ¡t c t;g aa;g a g;g0g;t c c ! t c a;g t c ¡t a c ! g t g;g t a;c c a
Affected <--- a!ag t!gg a!acg!g g g!tgt!c c c !g t c!at t!g cc!gt c !t ga!aga!gg g!t c c ! t ca!gt c !t a c!gt g!g ta!c ca
Figure 1.23 Continued an A to G substitution was found to change ATG to GTG (HBA1:c.1A>G) (Moi et al. 1987). The phenotypic consequences of the former were more severe due to the more prominent contribution of HBA2 versus HBA1 to normal a globin expression.
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