Age-Related Accumulation of Mutations Supports a Replication-Dependent Mechanism of Spontaneous Mutation at Tandem Repeat DNA Loci in Mice
Age-Related Accumulation of Mutations Supports a Replication-Dependent Mechanism of Spontaneous Mutation at Tandem Repeat DNA Loci in Mice
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DOI：
10.1093/molbev/msp182
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发表时间：
2009-11-01
影响因子：
10.7
通讯作者：
Dubrova, Yuri E.
中科院分区：
文献类型：
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作者：
Hardwick, Robert J.;Tretyakov, Michael V.;Dubrova, Yuri E.
扩展的简单串联重复序列（ESTR）基因座属于小鼠基因组中高度不稳定的基因座。在这些位点非常高的自发不稳定性的机制仍然知之甚少。本文用单分子聚合酶链反应比较了12、26、48和96周龄雄性小鼠不同增殖能力组织中突变积累的模式。在非增殖的大脑中，我们没有观察到任何可测量的与年龄相关的ESTR突变积累。相反，在老年小鼠的Ile精子样品中检测到ESTR突变频率的高度升高;在骨髓组织中也观察到类似的变化。年轻小鼠和老年小鼠的所有组织中积累的ESTR突变谱没有显著差异。总之，这些数据清楚地表明，自发ESTR突变几乎只发生在复制熟练的细胞。为了进一步了解ESTR突变的机制，我们建立了一个与年龄相关的突变累积的随机模型。假设ESTR突变率的值为0.01 - 0.04/细胞分裂，则观察到的在脑和精子中积累的ESTR突变体谱相当准确地近似。由于这些估计值大大超过了蛋白质编码基因和微卫星位点的估计值，因此我们的数据表明，ESTRs代表了哺乳动物基因组中最不稳定的位点之一。我们的研究结果还表明，ESTR基因座可以被视为一类扩展的微卫星，其自发突变的机制很可能归因于复制滑动。
Expanded simple tandem repeat (ESTR) loci belong to the class of highly unstable loci in the mouse genome. The mechanisms underlying the very high spontaneous instability at these loci still remain poorly understood. Using single-molecule polymerase chain reaction, here we have compared the pattern of mutation accumulation in tissues With different proliferation capacities in male mice of age 12, 26, 48, and 96 weeks. In the nonproliferating brain, we did not observe any measurable age-related accumulation of ESTR Mutations. In Contrast, a highly elevated frequency of ESTR mutation was detected in I lie sperm samples taken from old mice; similar changes were also observed ill the bone marrow tissue. The spectra of ESTR mutations accumulated ill all tissues of young and old mice did not significantly differ. Taken together, these data clearly imply that spontaneous ESTR mutations Occur almost exclusively in replication-proficient cells. To gain further insights into the mechanisms of ESTR mutation, we developed a stochastic model of age-related mutation accumulation. The observed spectra of ESTR mutants accumulated in the brain and sperm were fairly accurately approximated assuming the values of ESTR Mutation rate, ranging from 0.01 to 0.04 per cell division. As these estimates dramatically exceed those for protein-coding genes and microsatellite loci, our data therefore Suggest that ESTRs represent one of the most unstable loci in the mammalian genome. The results of our study also imply that ESTR loci can be regarded as a class of expanded microsatellites, with the mechanism of spontaneous Mutation most probably attributed to replication slippage.