  Background: There is a 3-fold redundancy in the Genetic Code; most amino
acids are encoded by more than one codon. These synonymous codons are not used
equally; there is a Codon Usage Bias (CUB). This article will provide novel
information about the origin and evolution of this bias.
  Results: Codon Usage Bias (CUB, defined here as deviation from equal usage of
synonymous codons) was studied in 113 species. The average CUB was 29.3 +/-
1.1% (S.E.M, n=113) of the theoretical maximum and declined progressively with
evolution and increasing genome complexity. A Pan-Genomic Codon Usage Frequency
(CUF) Table was constructed to describe genome-wide relationships among codons.
Significant correlations were found between the number of synonymous codons and
(i) the frequency of the respective amino acids (ii) the size of CUB. Numerous,
statistically highly significant, internal correlations were found among codons
and the nucleic acids they comprise. These strong correlations made it possible
to predict missing synonymous codons (wobble bases) reliably from the remaining
codons or codon residues.
  Conclusions: The results put the concept of "codon bias" into a novel
perspective. The internal connectivity of codons indicates that all synonymous
codons might be integrated parts of the Genetic Code with equal importance in
maintaining its functional integrity.
