Mutation Rates in Humans. II. Sporadic Mutation-Specific Rates and Rate of Detrimental Human Mutations Inferred from Hemophilia B

SummaryWe estimated the rates per base per generation of specific types of mutations, using our direct estimate of the overall mutation rate for hemophilia B and information on the mutations present in the United Kingdom's population as well as those reported year by year in the hemophilia B world database. These rates are as follows: transitions at CpG sites 9.7×10−8, other transitions 7.3×10−9, transversions at CpG sites 5.4×10−9, other transversions 6.9×10−9, and small deletions/insertions causing frameshifts 3.2×10−10. By taking into account the ratio of male to female mutation rates, the above figures were converted into rates appropriate for autosomal DNA—namely, 1.3×10−7, 9.9×10−9, 7.3×10−9, 9.4×10−9, 6.5×10−10, where the latter is the rate for all small deletion/insertion events. Mutation rates were also independently estimated from the sequence divergence observed in randomly chosen sequences from the human and chimpanzee X and Y chromosomes. These estimates were highly compatible with those obtained from hemophilia B and showed higher mutation rates in the male, but they showed no evidence for a significant excess of transitions at CpG sites in the spectrum of Y-sequence divergence relative to that of X-chromosome divergence. Our data suggest an overall mutation rate of 2.14×10−8 per base per generation, or 128 mutations per human zygote. Since the effective target for hemophilia B mutations is only 1.05% of the factor IX gene, the rate of detrimental mutations, per human zygote, suggested by the hemophilia data is ∼1.3