Substantial regional variation in substitution rates in the human genome: Importance of GC content, gene density, and telomere-specific effects
Substantial regional variation in substitution rates in the human genome: Importance of GC content, gene density, and telomere-specific effects
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DOI：
10.1007/s00239-004-0222-5
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发表时间：
2005-06-01
影响因子：
3.9
通讯作者：
Petrov, DA
中科院分区：
文献类型：
--
作者：
Arndt, PF;Hwa, T;Petrov, DA
这项研究提出了第一个全球性的，1兆碱基水平的分析模式的核苷酸取代沿着人类血统。这项研究的基础是对自哺乳动物辐射以来沉积在人类基因组中的大量重复元件进行分析，得出了一些使用更传统的比较分析方法难以获得的结果。这一分析表明，替代率存在着巨大而一致的差异，不同区域之间的差异最高可达两倍。C或G核苷酸被A或T核苷酸取代的速率比反向速率的变化要剧烈得多，这表明这种变化在很大程度上是由于突变速率的差异，而不是整个基因组中C/G与A/T核苷酸固定的概率。对于所有类型的取代，我们观察到显著多于冷点的热点，其中热点显示出超过数十Mbp的显著聚类。我们的分析表明，周围序列的GC含量是替代率的最佳预测因子。与基因组的其余部分相比，端粒附近的取代模式似乎非常不同，并且不能用取代率与GC含量或外显子密度的全基因组相关性来解释。端粒取代模式与自然选择或偏向基因转换一致，其作用是增加距离端粒10-15 Mbp内的序列的GC含量。
This study presents the first global, 1-Mbp-level analysis of patterns of nucleotide substitutions along the human lineage. The study is based on the analysis of a large amount of repetitive elements deposited into the human genome since the mammalian radiation, yielding a number of results that would have been difficult to obtain using the more conventional comparative method of analysis. This analysis revealed substantial and consistent variability of rates of substitution, with the variability ranging up to twofold among different regions. The rates of substitutions of C or G nucleotides with A or T nucleotides vary much more sharply than the reverse rates, suggesting that much of that variation is due to differences in mutation rates rather than in the probabilities of fixation of C/G vs. A/T nucleotides across the genome. For all types of substitution we observe substantially more hotspots than coldspots, with hotspots showing substantial clustering over tens of Mbp's. Our analysis revealed that GC-content of surrounding sequences is the best predictor of the rates of substitution. The pattern of substitution appears very different near telomeres compared to the rest of the genome and cannot be explained by the genome-wide correlations of the substitution rates with GC content or exon density. The telomere pattern of substitution is consistent with natural selection or biased gene conversion acting to increase the GC-content of the sequences that are within 10-15 Mbp away from the telomere.