The genome-wide determinants of human and chimpanzee microsatellite evolution
The genome-wide determinants of human and chimpanzee microsatellite evolution
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DOI：
10.1101/gr.7113408
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发表时间：
2008-01-01
期刊：
影响因子：
7
通讯作者：
Makova, Kateryna D.
中科院分区：
文献类型：
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作者：
Kelkar, Yogeshwar D.;Tyekucheva, Svitlana;Makova, Kateryna D.
微卫星的突变率在不同位点间差异很大。这种异质性的原因在很大程度上仍然是谜，但对于理解许多人类神经疾病和癌症遗传不稳定性至关重要。在这项首次全基因组研究中，利用重采样和回归技术研究了人类-黑猩猩同源微卫星的内在特征和区域基因组因素对易变性变异的相对贡献。因此，我们揭示了微卫星诱变的复杂性如下。首先，内在特征（重复次数、长度和基序大小）都影响滑动的概率和速率，是最强有力的可变性预测因子。其次，易变性随着长度的增加而不均匀地增加，这表明除了滑移之外的过程，如错误修复，也会导致突变。第三，不同基序组成的微卫星的易变性不同，可能是由于它们的滑动中间体形成的二级DNA结构不同。第四，单核苷酸微卫星的易变性受到其在性染色体上与常染色体上以及Alu重复序列内外的位置的影响，前者证实了复制的重要性，后者提示了基因转换的作用。第五，转录状态和在特定等差内的位置不会影响微卫星的易变性。第六，与内在特征相比，区域基因组因素的影响较小。最后，我们的回归模型解释了近90%的微卫星变异，可以为人类疾病、法医学和保护遗传学的研究产生有用的预测。
Mutation rates of microsatellites vary greatly among loci. The causes of this heterogeneity remain largely enigmatic yet are crucial for understanding numerous human neurological diseases and genetic instability in cancer. In this first genome-wide study, the relative contributions of intrinsic features and regional genomic factors to the variation in mutability among orthologous human-chimpanzee microsatellites are investigated with resampling and regression techniques. As a result, we uncover the intricacies of microsatellite mutagenesis as follows. First, intrinsic features (repeat number, length, and motif size), which all influence the probability and rate of slippage, are the strongest predictors of mutability. Second, mutability increases nonuniformly with length, suggesting that processes additional to slippage, such as faulty repair, contribute to mutations. Third, mutability varies among microsatellites with different motif composition likely due to dissimilarities in secondary DNA structure formed by their slippage intermediates. Fourth, mutability of mononucleotide microsatellites is impacted by their location on sex chromosomes vs. autosomes and inside vs. outside of Alu repeats, the former confirming the importance of replication and the latter suggesting a role for gene conversion. Fifth, transcription status and location in a particular isochore do not influence microsatellite mutability. Sixth, compared with intrinsic features, regional genomic factors have only minor effects. Finally, our regression models explain similar to 90% of variation in microsatellite mutability and can generate useful predictions for the studies of human diseases, forensics, and conservation genetics.