Nonrandom patterns of codon usage and of nucleotide substitutions in human a- and 18-globin genes: An evolutionary strategy reducing the rate of mutations with drastic effects?

Nucleotide substitutions within a structural gene can cause two principal "drastic" phenotypic effects at the protein level: translatable -+ untranslatable and nonpolar hydrophobic + hydrophilic amino acid substitutions. The sequence of nucleotides in the structural human a- and f3-globin genes and their variants were examined to determine whether codon usage, patterns of nucleotide substitutions, or both, reduced the relative and absolute rates of these unfavorable mutations. Based on translation of abnormal hemoglobins, it is likely that all 61 nontermi- nation codons are potentially translatable, though only 47 are nor-mally used. Moreover, codons that can mutate to a termination codon are never used whenever the corresponding amino acid is specified also by triplets that cannot mutate to termination by a single-step mutation. Thus, the number of opportunities to mutate to an untranslatable codon is reduced to the minimum compatible with the amino acid composition of these chains. The relative rates of U + non-U substitutions were much lower than those of other substitutions. Because U residues must be involved in most termination mutations and in all nonpolar hydrophobic + hydro- philic amino acid substitutions, there is a considerable reduction of mutational events, causing drastic phenotypic effects. These findings are likely to be the end result of evolutionary selection by yet unknown mechanisms. expected; non-U--U: 37 observed vs. 61.5 expected; P <<0.001). This attenuation is the expected consequence of the relative enrichment of the U++non-U substitutions among the drastic (i.e., pathologic) missense codon substitutions.