Box Codon position and degeneracy

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).

Missense Conservative

(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

HBB:c.52A>T

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

agtg!gat!cgg!ggt!gtc!ccg!tca!ttg!ccg!tct!gaa!gag!gag!tcc!tca!gtc!tac!gtg!gta!cca

Substitution results in UAG nonsense codon

Affected

Normal

Affected

(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

Frameshift results in UGA nonsense codon

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.

0 0

Post a comment