The rate of CpG mutation in Alu repetitive elements within the p53 tumor suppressor gene in the primate germline.
The rate of CpG mutation in Alu repetitive elements within the p53 tumor suppressor gene in the primate germline.
复制标题
灵长类种系 p53 肿瘤抑制基因内 Alu 重复元件的 CpG 突变率。
DOI：
10.1006/jmbi.1996.0246
复制
发表时间：
1996
期刊：
影响因子：
--
通讯作者：
Jones,PA
中科院分区：
文献类型：
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作者：
Yang,AS;Gonzalgo,ML;Zingg,JM;Millar,RP;Buckley,JD;Jones,PA
CpG二核苷酸上的胞嘧啶到胸腺嘧啶的过渡突变是癌症和遗传疾病中最常见的点突变。我们计算了灵长类动物生殖系中CpG突变的频率，方法是推导出3500万至5500万年前插入灵长类动物p53基因6内含子的analurepeat元件的原始一致序列。将这一原始序列与现今灵长类动物6内含子中的alussequence进行比较，以确定进化过程中发生的突变的性质和速率。我们估计CpG核苷酸的半衰期为2400万年至6000万年，该二核苷酸的突变速率常数为1.2 × 10−8至2.9 × 10−8年−1。这些结果被p53基因内含子10的第二个使用序列的分析所证实。它们的胞内突变速率比它们在双链DNA中5-甲基胞嘧啶脱胺的体外化学速率至少慢1250倍，这表明目前对CpG突变修复的估计被严重低估了。此外，CpG二核苷酸的易变性导致了脊椎动物基因组中CpG二核苷酸的枯竭，本研究的计算表明，灵长类基因组中CpG二核苷酸的当前水平非常接近稳态平衡，即CpG突变率等于随机突变形成CpG的速率。
Cytosine to thymine transition mutations at the CpG dinucleotide are the most common point mutations in cancer and genetic disease. We calculated thein vivorate of CpG mutation in the primate germline by deriving a primordial consensus sequence for anAlurepetitive element which inserted into intron 6 of the primate p53 gene 35 to 55 million years ago. Comparison of this primordial sequence to theAlusequence in intron 6 of present-day primates was used to determine the nature and rate of mutations which occurred during evolution. We estimate the half-life of a CpG nucleotide to be 24 to 60 million years, and the rate constant for mutation at this dinucleotide to be 1.2 × 10−8to 2.9 × 10−8years−1. These results were confirmed by the analysis of a secondAlusequence in intron 10 of the p53 gene. Thein vivomutation rate is at least 1250-fold slower than thein vitrochemical rate of 5-methylcytosine deamination in double-stranded DNA, showing that current estimates of CpG mutation repair have been significantly underestimated. Furthermore, the mutability of the CpG dinucleotide has led to the depletion of this dinucleotide from the vertebrate genome, and calculations in this study suggest that current levels of the CpG dinucleotide in the primate genome are very close to a steady state equilibrium in which the rate of CpG mutation is equal to the rate of CpG formation by random mutation.