Kondrashov Alexey S
National Center for Biotechnology Information, NIH, Bethesda, Maryland 20892, USA.
Hum Mutat. 2003 Jan;21(1):12-27. doi: 10.1002/humu.10147.
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 1.8x10(-8) per nucleotide per generation, and the coefficient of variation of this rate across the 20 loci is 0.53. Single nucleotide substitutions are approximately 25 times more common than all other mutations, deletions are approximately 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 5x10(-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.
我直接根据导致常染色体显性疾病的8个基因座以及导致X连锁疾病的12个基因座上的每基因座突变率数据，以及新生无义核苷酸替换、缺失、插入和复杂事件的序列数据，估算了人类不同类型自发突变的每核苷酸突变率。结果与通过比较直系同源的人类和黑猩猩假基因获得的间接估计结果高度一致。所有突变综合率的平均直接估计值为每代每核苷酸1.8×10⁻⁸，该率在20个基因座上的变异系数为0.53。单核苷酸替换比所有其他突变大约常见25倍，缺失比插入大约常见3倍，复杂突变非常罕见，并且CpG环境使替换率提高一个数量级。每基因座突变率高的基因座也具有较高的每核苷酸替换率的趋势仅为中等程度，并且缺失和插入的每核苷酸率与每基因座突变率在统计上相互独立。不同类型突变的发生率在各基因座之间高度相关。每核苷酸率高于5×10⁻⁷的突变热点对人类突变的贡献很小。在未来十年中，直接测量将对DNA水平上的人类自发突变产生相当精确的定量描述。
