Direct estimates of human per nucleotide mutation rates at 20 loci causing mendelian diseases

I estimate per nucleotide rates of spontaneous mutations of different kinds in humans directly from the data on per locus mutation rates and on sequences of de novo nonsense nucleotide substitutions, deletions, insertions, and complex events at eight loci causing autosomal dominant diseases and 12 loci causing X‐linked diseases. The results are in good agreement with indirect estimates, obtained by comparison of orthologous human and chimpanzee pseudogenes. The average direct estimate of the combined rate of all mutations is 1.8×10 −8 per nucleotide per generation, and the coefficient of variation of this rate across the 20 loci is 0.53. Single nucleotide substitutions are ∼25 times more common than all other mutations, deletions are ∼three times more common than insertions, complex mutations are very rare, and CpG context increases substitution rates by an order of magnitude. There is only a moderate tendency for loci with high per locus mutation rates to also have higher per nucleotide substitution rates, and per nucleotide rates of deletions and insertions are statistically independent on the per locus mutation rate. Rates of different kinds of mutations are strongly correlated across loci. Mutational hot spots with per nucleotide rates above 5×10 −7 make only a minor contribution to human mutation. In the next decade, direct measurements will produce a rather precise, quantitative description of human spontaneous mutation at the DNA level. Hum Mutat 21:12–27, 2002. Published 2002 Wiley‐Liss, Inc.