The proportion of all point mutations which are unacceptable: an estimate based on hemoglobin amino acid and...

Statistical analysis of the distribution of 156 kinds of human hemoglobin beta (Hbbeta) chain variants suggests that mutations are essentially random in their location. Thus differential fitness, not differential mutability, is the principal source of nonrandom distribution of interspecies differences in Hbbeta amino acid sequence. Similar analyses of both the location and the kind of interspecies differences detected among primates support this viewpoint and lead us to estimate that at least 95% of all amino acid subsitutions,i.e., nonsynonymous mutations, in Hbbeta are functionally unacceptable in homozygous state. Through the combined use of this estimate and the number of nonsynonymous and synonymous substitutions per nucleotide site inferred from comparisons of entire human and rabbit HbbetamRNA nucleotide sequences, we calculate (a) approximately 70% of synonymous Hbbeta mutations are adaptively undersirable and (b) the mutation rate underlying all changes is lesser than or equal to 10(-8) nucleotide substitutions per nucleotide site per year. Apart from such calculations, analyses of nucleotide patterns in HbbetamRNA as well as in rat preproinsulin mRNA reinforce the notion that a large portion of synonymous mutations are functionally unacceptable and rendered so by selective constraint, at a pretranslational level, of the abundance of particular nucleotide doublets such as CpG.