Why does the human factor IX gene have a G + C content of 40%?

The factor IX gene has a G + C content of approximately 40% in all mammalian species examined. In human factor IX, C→T and G→A transitions at the dinucleotide CpG are elevated at least 24-fold relative to other transitions. Can the G + C content be explained solely by this hot spot of mutation? Using our mathematical model, we show that the elevation of mutation at CpG cannot alone lower the G + C content below 45%. To search for other hot spots of mutation that might contribute to the reduction of G + C content, we assessed the relative rates of base substitution in our sample of 160 families with hemophilia B. Seventeen independent single-base substitutions are reported herein for a total of 96 independent point mutations in our sample. The following conclusions emerge from the analysis of our data and, where appropriate, the data of others: (1) Transversions at CpG are elevated an estimated 7.7-fold relative to other transversions. (2) The mutation rates at non-CpG dinucleotides are remarkably uniform; none of the observed rates are either more than twofold above the median for transitions or more than threefold above the median for transversions. (3) The pattern of recent mutation is compatible with the pattern during mammalian evolution that has maintained the G + C content of the factor IX gene at approximately 40%.