Neutral substitutions occur at a faster rate in exons than in noncoding DNA in primate genomes
Neutral substitutions occur at a faster rate in exons than in noncoding DNA in primate genomes
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DOI：
10.1101/gr.1152803
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发表时间：
2003-05-01
期刊：
影响因子：
7
通讯作者：
Kumar, S
中科院分区：
文献类型：
--
作者：
Subramanian, S;Kumar, S
外显子（同义位点）和非编码区（内含子和基因间）的点突变率通常被认为是相同的。然而，外显子（81个基因）和人类和黑猩猩基因组的长基因间片段（141.3 kbp）的同义替换的比较序列分析显示，外显子中的突变率比非编码DNA高30%-60%。我们提出了一个差异CpG含量假说来解释这一基本的，似乎不直观的模式。我们发现，增加外显子率是CpG二核苷酸中涉及的同义位点相对过剩的结果，因为非CpG位点的进化趋异在非编码DNA和外显子的同义位点中是相似的。我们的假设的预期和预测得到了证实，比较涉及更远的相关物种，包括人类猩猩，人类狒狒，和人类猕猴。我们的研究结果表明，在GC丰富的基因组区域的突变率较高的潜在机制，预测假基因随着时间的推移突变的非线性积累，并提供了一个可能的解释观察到的较高的多样性单核苷酸多态性（SNP）的同义位点的外显子相比，非编码区。
Point mutation rates in exons (synonymous sites) and noncoding (introns and intergenic) regions are generally assumed to be the same. However, comparative sequence analyses of synonymous substitutions in exons (81 genes) and that of long intergenic fragments (141.3 kbp) of human and chimpanzee genomes reveal a 30%-60% higher mutation rate in exons than in noncoding DNA. We propose a differential CpG content hypothesis to explain this fundamental, and seemingly unintuitive, pattern. We find that the increased exonic rate is the result of the relative overabundance of synonymous sites involved in CpG dinucleotides, as the evolutionary divergence in non-CpG sites is similar in noncoding DNA and synonymous sites of exons. Expectations and predictions of our hypothesis are confirmed in comparisons involving more distantly related species, including human-orangutan, human-baboon, and human-macaque. Our results suggest an underlying mechanism for higher mutation rate in GC-rich genomic regions, predict nonlinear accumulation of mutations in pseudogenes over time, and provide a possible explanation for the observed higher diversity of single nucleotide polymorphisms (SNPs) in the synonymous sites of exons compared to the noncoding regions.