Eckert Kristin A, Hile Suzanne E
Department of Pathology, The Jake Gittlen Cancer Research Foundation, The Pennsylvania State University College of Medicine, 500 University Drive, PA, USA.
Mol Carcinog. 2009 Apr;48(4):379-88. doi: 10.1002/mc.20499.
Microsatellite sequences are ubiquitous in the human genome and are important regulators of genome function. Here, we examine the mutational mechanisms governing the stability of highly abundant mono-, di-, and tetranucleotide microsatellites. Microsatellite mutation rate estimates from pedigree analyses and experimental models range from a low of approximately 10(-6) to a high of approximately 10(-2) mutations per locus per generation. The vast majority of observed mutational variation can be attributed to features intrinsic to the allele itself, including motif size, length, and sequence composition. A greater than linear relationship between motif length and mutagenesis has been observed in several model systems. Motif sequence differences contribute up to 10-fold to the variation observed in human cell mutation rates. The major mechanism of microsatellite mutagenesis is strand slippage during DNA synthesis. DNA polymerases produce errors within microsatellites at a frequency that is 10- to 100-fold higher than the frequency of frameshifts in coding sequences. Motif sequence significantly affects both polymerase error rate and specificity, resulting in strand biases within complementary microsatellites. Importantly, polymerase errors within microsatellites include base substitutions, deletions, and complex mutations, all of which produced interrupted alleles from pure microsatellites. Postreplication mismatch repair efficiency is affected by microsatellite motif size and sequence, also contributing to the observed variation in microsatellite mutagenesis. Inhibition of DNA synthesis within common microsatellites is highly sequence-dependent, and is positively correlated with the production of errors. DNA secondary structure within common microsatellites can account for some DNA polymerase pause sites, and may be an important factor influencing mutational specificity.
微卫星序列在人类基因组中普遍存在，是基因组功能的重要调节因子。在这里，我们研究了控制高度丰富的单核苷酸、二核苷酸和四核苷酸微卫星稳定性的突变机制。来自家系分析和实验模型的微卫星突变率估计范围从低至约每代每个位点10^(-6) 到高至约10^(-2) 次突变。绝大多数观察到的突变变异可归因于等位基因本身的内在特征，包括基序大小、长度和序列组成。在几个模型系统中已观察到基序长度与诱变之间存在大于线性的关系。基序序列差异对人类细胞突变率中观察到的变异贡献高达10倍。微卫星诱变的主要机制是DNA合成过程中的链滑动。DNA聚合酶在微卫星内产生错误的频率比编码序列中移码的频率高10到100倍。基序序列显著影响聚合酶错误率和特异性，导致互补微卫星内的链偏向。重要的是，微卫星内的聚合酶错误包括碱基替换、缺失和复杂突变，所有这些都会从纯微卫星产生中断的等位基因。复制后错配修复效率受微卫星基序大小和序列的影响，也导致了观察到的微卫星诱变变异。常见微卫星内DNA合成的抑制高度依赖序列，并且与错误的产生呈正相关。常见微卫星内的DNA二级结构可以解释一些DNA聚合酶暂停位点，并且可能是影响突变特异性的重要因素。
