Wide intra-genomic G+C heterogeneity in human and chicken is mainly due to strand-symmetric directional mutation pressures: dGTP-oxidation and symmetric cytosine-deamination hypotheses.

The intra-strand Parity Rule 2 of DNA (PR2) states that A=T and G=C within each strands. Useful corollaries of PR2 are G/(G+C)=A/(A+T)=0.5, G/(G+A)=C/(C+T)=G+C, G/(G+T)=C/(C+A)=G+C. Here. A, T, G, and C represent relative contents of the four nucleotide residues in a specific strand of DNA, so that A+T+G+C=1. Thus, deviations from the PR2 is a sign of strand-specific (or asymmetric) mutation and/or selection pressures. The present study delineates the symmetric and asymmetric effects of mutations on the intra-genomic heterogeneity of the G+C content in the human genome. The results of this study on the human genome are: (1) When both two- and four-codon amino acids were combined, only slight departures from the PR2 were observed in the total ranges of G+C content of the third-codon position. Thus, the G+C heterogeneity is likely to be caused by symmetric mutagenesis between the two strands. (2) The above result makes the deamination of cytosine due to double-strand breathing of DNA [Mol. Biol. Evol. 17 (2000) 1371] and/or incorporation of the oxidized guanine (8-oxo-guanine) opposite adenine during DNA replication (dGTP-oxidation hypothesis) as the most likely candidates for the major cause of the diversities of the G+C content. (3) Patterns of amino acid-specific PR2-biases detected by plotting PR2 corollaries against the G+C content of third codon position revealed that eight four-codon amino acids can be divided into three types by the second codon letter: (a) C(2)-type (Ala, Pro, Ser4, and Thr), (b) G(2)-type (Arg4 and Gly), and (c) T(2)-type (Leu4 and Val). (4) Most of the asymmetric plot patterns of the above three classes in PR2 biases can be explained by C(2)-->T(2) deamination of C(2)pG(3) of C(2)-type to T(2)pG(3) (T(2)-type) in both human and chicken. This explains the existence of some preferred codons in human and chicken. However, these biases (asymmetric) hardly contribute to the overall G+C content diversity of the third codon position.