Mutation rates in humans. II. Sporadic mutation-specific rates and rate of detrimental human mutations inferred from hemophilia B

Am J Hum Genet. 1999 Dec;65(6):1580-7. doi: 10.1086/302652.

Abstract

We 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 9.7x10-8, other transitions 7.3x10-9, transversions at CpG sites 5.4x10-9, other transversions 6.9x10-9, and small deletions/insertions causing frameshifts 3.2x10-10. By taking into account the ratio of male to female mutation rates, the above figures were converted into rates appropriate for autosomal DNA-namely, 1.3x10-7, 9.9x10-9, 7.3x10-9, 9.4x10-9, 6.5x10-10, 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 2.14x10-8 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 approximately 1.3.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CpG Islands / genetics
  • DNA Mutational Analysis
  • Databases, Factual
  • Evolution, Molecular
  • Factor IX / genetics
  • Female
  • Gene Frequency / genetics
  • Genome, Human
  • Hemophilia B / genetics*
  • Humans
  • Male
  • Mutation / genetics*
  • Pan troglodytes / genetics
  • Phenotype
  • Sex Characteristics
  • United Kingdom
  • X Chromosome / genetics
  • Y Chromosome / genetics
  • Zygote / metabolism

Substances

  • Factor IX