De novo mutations producing unstable Hbs or Hbs M.: II. Direct Estimates of Minimum Nucleotide Mutation Rates in Man

Cases of unstable hemoglobin and hemoglobin M disease that have appeared as de novo mutants over a span of approximately 50 years were used in derivingminimal, direct estimates of mutation rates per nucleotide per generation in man. The estimates are based upon analysis of data related to 40 cases of unstable Hbs and 15 of Hbs M that arose in 13 countries. The estimated rate calculated using all de novo β-gene mutants is 7.4×10-9 per nucleotide per generation; that derived using de novo α-gene mutants is 10.0×10-9. Subsequent calculations of mutation rates per α- and β-chain gene and extrapolation of these rates to a hypothetical gene of 1000 nucleotides yield an estimated mutation rate of 8.6×10-6 per 1000 nucleotides per generation. Even though some instances of false paternity may have biased these estimates in an upward direction, underreporting of Hb M cases, and particularly of unstable hemoglobins, makes it likely that the cited values are minimal estimates of mutation rates at the molecular level.