title: Mutation rates in humans. II. Sporadic mutation-specific rates and rate of detrimental human mutations inferred from hemophilia B.
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.
authors.affiliation: Division of Medical and Molecular Genetics, Guy's, King's, and St. Thomas' School of Medicine, Guy's Campus, London SE1 9RT, United Kingdom. francesco.giannelli@kcl.ac.uk.
authors.forename: F
authors.initials: F
authors.lastname: Giannelli
authors.forename: T
authors.initials: T
authors.lastname: Anagnostopoulos
authors.forename: P M
authors.initials: PM
authors.lastname: Green
mesh_terms: D000818:Animals; D018899:CpG Islands / Q000235:genetics; D004252:DNA Mutational Analysis; D016208:Databases, Factual; D019143:Evolution, Molecular; D005164:Factor IX / Q000235:genetics; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D015894:Genome, Human; D002836:Hemophilia B / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics*; D002679:Pan troglodytes / Q000235:genetics; D010641:Phenotype; D012727:Sex Characteristics; D006113:United Kingdom; D014960:X Chromosome / Q000235:genetics; D014998:Y Chromosome / Q000235:genetics; D015053:Zygote / Q000378:metabolism
chemical_list: D005164:Factor IX