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

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Abstract
Nucleotide substitutions within a structural gene can cause 2 principal drastic phenotypic effects at the protein level: translatable .fwdarw. untranslatable and nonpolar hydrophobic .tautm. hydrophilic amino acid substitutions. The sequence of nucleotides in the structural human .alpha.- and .beta.-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 Hb it is likely that all 61 nontermination codons are potentially translatable, though only 47 are normally used. 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. 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 .tautm. 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 .tautm. hydrophilic 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.