Degeneracy of the genetic code

The genetic code has redundancy but no ambiguity (see the codon tables above for the full correlation). For example, although codons GAA and GAG both specify glutamic acid (redundancy), neither of them specifies any other amino acid (no ambiguity). The codons encoding one amino acid may differ in any of their three positions. For example the amino acid glutamic acid is specified by GAA and GAG codons (difference in the third position), the amino acid leucine is specified by UUA, UUG, CUU, CUC, CUA, CUG codons (difference in the first or third position), while the amino acid serine is specified by UCA, UCG, UCC, UCU, AGU, AGC (difference in the first, second or third position).
A position of a codon is said to be a fourfold degenerate site if any nucleotide at this position specifies the same amino acid. For example, the third position of the
glycine codons (GGA, GGG, GGC, GGU) is a fourfold degenerate site, because all nucleotide substitutions at this site are synonymous, i.e. they do not change the amino acid. Only the third positions of some codons may be fourfold degenerate. A position of a codon is said to be a twofold degenerate site if only two of four possible nucleotides at this position specify the same amino acid. For example, the third position of the glutamic acid codons (GAA, GAG) is a twofold degenerate site, so is the first position of the leucine codons (UCA, UCC, CCU, CCC, CCA, CCG). In twofold degenerate sites, the equivalent nucleotides are always either two purines (A/G) or two pyrimidines (C/U), so only transversional substitutions (purine to pyrimidine or pyrimidine to purine) in twofold degenerate sites are nonsynonymous. A position of a codon is said to be a non-degenerate site if any mutation at this position results in amino acid substitution. There is only one threefold degenerate site where changing three of the four nucleotides has no effect on the amino acid, while changing the fourth possible nucleotide results in an amino acid substitution. This is the third position of an isoleucine codon: AUU, AUC, or AUA all encode isoleucine, but AUG encodes methionine. In computation this position is often treated as a twofold degenerate site.
There are three amino acids encoded by six different codons:
serine, leucine, arginine. Only two amino acids are specified by a single codon; one of these is the amino-acid methionine, specified by the codon AUG, which also specifies the start of translation; the other is tryptophan, specified by the codon UGG. The degeneracy of the genetic code is what accounts for the existence of silent mutations.
Degeneracy results because a triplet code designates 20 amino acids and a stop codon. Because there are four bases, triplet codons are required to produce at least 21 different codes. For example, if there were two bases per codon, then only 16 amino acids could be coded for (4²=16). Because at least 21 codes are required, then 4³ gives 64 possible codons, meaning that some degeneracy must exist.
These properties of the genetic code make it more fault-tolerant for
point mutations. For example, in theory, fourfold degenerate codons can tolerate any point mutation at the third position, although codon usage bias restricts this in practice in many organisms; twofold degenerate codons can tolerate one out of the three possible point mutations at the third position. Since transition mutations (purine to purine or pyrimidine to pyrimidine mutations) are more likely than transversion (purine to pyrimidine or vice-versa) mutations, the equivalence of purines or that of pyrimidines at twofold degenerate sites adds a further fault-tolerance.

Grouping of codons by amino acid residue molar volume and hydropathy.
A practical consequence of redundancy is that some errors in the genetic code only cause a silent mutation or an error that would not affect the protein because the
hydrophilicity or hydrophobicity is maintained by equivalent substitution of amino acids; for example, a codon of NUN (where N = any nucleotide) tends to code for hydrophobic amino acids. NCN yields amino acid residues that are small in size and moderate in hydropathy; NAN encodes average size hydrophilic residues; UNN encodes residues that are not hydrophilic.[3][4]
Even so, single point mutations can still cause dysfunctional proteins. For example, a mutated hemoglobin gene causes sickle-cell disease. In the mutant hemoglobin a hydrophilic glutamate (Glu) is substituted by the hydrophobic valine (Val), which reduces the solubility of β-globin. In this case, this mutation causes hemoglobin to form linear polymers linked by the hydrophobic interaction between the valine groups causing sickle-cell deformation of erythrocytes. Sickle-cell disease is generally not caused by a de novo mutation. Rather it is selected for in malarial regions (in a way similar to thalassemia), as heterozygous people have some resistance to the malarial Plasmodium parasite (heterozygote advantage).
These variable codes for amino acids are allowed because of modified bases in the first base of the
anticodon of the tRNA, and the base-pair formed is called a wobble base pair. The modified bases include inosine and the Non-Watson-Crick U-G basepair.


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