Feng Jinong, Drost Joni B, Scaringe William A, Liu Qiang, Sommer Steve S
Department of Molecular Genetics, City of Hope National Medical Center, Duarte, California.
Hum Mutat. 2002 Jan;19(1):49-57. doi: 10.1002/humu.10018.
Pollutants and dietary mutagens have been associated with somatic mutation and cancer, but the extent of their influence on germline mutation is not clear. Since deleterious germline mutations can be transmitted for thousands of years, any influence on germline mutation from the vast increase in man-made chemicals of the past 150 years would be an important public health issue. Observed disease causing mutations in the X-linked factor IX gene (F9) of hemophilia B patients originated predominantly in the past 150 years, since the half-life of these mutations in human populations had been about two generations before effective treatment became available about a generation ago. Recent changes in germline mutational processes may be detected by comparison of the observed hemophilia B causing mutation pattern in F9 with the pattern of neutral polymorphisms which occurred over a much longer period of time. By scanning a total of 1.5 megabases of deep intronic regions of F9 in the genomic DNA from 84 individuals, 42 neutral polymorphisms were found in 23 haplotypes that differed by at least 11 mutations from the ancestral primate haplotype. By sequencing F9 in seven non-human primates, 39 of these polymorphisms were characterized as ancient mutations relative to a unanimous ancestral primate allele. This ancient mutation pattern was compared to the recent pattern of hemophilia B causing mutations. Remarkably, no significant difference was found (P=0.5), suggesting that the vast increase in man-made chemicals during the past 150 years has not had a major impact on the pattern of human germline mutation. This result is consistent with the hypothesis that endogenous processes dominate germline mutation.
污染物和膳食诱变剂与体细胞突变及癌症有关，但它们对生殖系突变的影响程度尚不清楚。由于有害的生殖系突变可以遗传数千年，过去150年中人造化学物质的大量增加对生殖系突变的任何影响都将是一个重要的公共卫生问题。观察到的血友病B患者X连锁因子IX基因（F9）中的致病突变主要起源于过去150年，因为在大约一代人之前有效治疗出现之前，这些突变在人群中的半衰期约为两代人。通过比较在F9中观察到的导致血友病B的突变模式与在更长时间段内发生的中性多态性模式，可以检测生殖系突变过程的近期变化。通过扫描来自84个人的基因组DNA中F9的总共1.5兆碱基的内含子深区，在23个单倍型中发现了42个中性多态性，这些单倍型与祖先灵长类单倍型至少有11个突变差异。通过对7种非人类灵长类动物的F9进行测序，相对于一致的祖先灵长类等位基因，这些多态性中有39个被表征为古老突变。将这种古老的突变模式与导致血友病B的近期突变模式进行了比较。值得注意的是，未发现显著差异（P = 0.5），这表明过去150年中人造化学物质的大量增加对人类生殖系突变模式没有重大影响。这一结果与内源性过程主导生殖系突变的假设一致。
