CYTOSINE METHYLATION AND THE FATE OF CPG DINUCLEOTIDES IN VERTEBRATE GENOMES
CYTOSINE METHYLATION AND THE FATE OF CPG DINUCLEOTIDES IN VERTEBRATE GENOMES
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DOI：
10.1007/bf00286715
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发表时间：
1989-09-01
期刊：
影响因子：
5.3
通讯作者：
KRAWCZAK, M
中科院分区：
文献类型：
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作者：
COOPER, DN;KRAWCZAK, M
二核苷酸CpG是人类基因组中突变的“热点”，这是由于（1）细胞DNA甲基转移酶对5“胞嘧啶的修饰和（2）随后5-甲基胞嘧啶（5 mC）自发脱氨为胸苷的高频率。因此，DNA甲基化对人类遗传疾病的发病率有重要影响，尽管是间接的。我们首次尝试从体外测定的5 mC脱氨基速率和细胞G/T错配修复系统的已知错误频率来估计5 mC的体内脱氨基速率。然后通过与临床数据进行比较来评估该估计值（md）的准确性和实用性，并且改进了md的估计值（1.66 ± 1.66）。10-16 s-1）。比较人、黑猩猩和猕猴的珠蛋白基因和假基因序列所显示的CpG突变率，进一步估计了md，所有这些都与第一个一致。然后在数学模型中使用该值允许估计产生目前在脊椎动物基因组的“散装DNA”中发现的“CpG抑制”水平所需的时间长度。这一时间跨度约为4.5亿年，与脊椎动物出现和适应性辐射的估计时间密切相关，因此与高度甲基化基因组的可能出现相吻合。5 mC脱氨速率的准确估计不仅对临床医学而且对基因进化的研究都是重要的。我们的数据表明，脊椎动物基因甲基化的模式可能是相对稳定的相对较长的进化时间，和CpG脱氨基的速率，在某些有限的条件下，可以作为一个“分子钟”。
The dinucleotide CpG is a "hotspot" for mutation in the human genomine as a result of (1) the modification of the 5'' cytosine by cellular DNA methyltransferases and (2) the consequent high frequency of spontaneous deamination of 5-methyl cytosine (5mC) to thymidine. DNA methylation thus contributes significantly, albeit indirectly, to the incidence of human genetic disease. We have attempted to estimate for the first time the in vivo rate of deamination of 5mC from the measured rate of 5mC deamination in vitro and the known error frequency of the cellular G/T mismatch-repair system. The accuracy and utility of this estimate (md) was then assessed by comparison with clinical data, and an improved estimated of md (1.66 .+-. 10-16 s-1) was derived. Comparison of the CpG mutation rates exhibited by globin gene and pseudogene sequences from human, chimpanzee and macaque provided further estimates of md, all of which were consistent with the first. Use of this value in a mathematical model then permitted the estimation of the length of time required to produce the level of "CpG suppression" currently found in the "bulk DNA" of vertebrate genomes. This time span, approximately 450 million years, corresponds closely to the estimated time since the emergence and adaptive radiation of the vertebrates and thus coincides with the probable advent of heavily methylated genomes. An accurate estimate of the 5mC deamination rate is important not only for clinical medicine but also for studies of gene evolution. Our data suggest both that patterns of vertebrate gene methylation may be comparatively stable over relative long periods of evolutionary time, and that the rate of CpG deamination can, under certain limited conditions, serve as a "molecular clock".