The C:G > T:A substitution at the CpG dinucleotide contexts is the most frequent substitution type in genome evolution. The mutational process is obviously ongoing in the human germline; however, its impact on common and rare genomic polymorphisms has not been comprehensively investigated yet. Here we observed the landscape and dynamics of C:G > T:A substitutions from population-scale human genome sequencing datasets including ~ 4300 whole-genomes from the 1000 Genomes and the pan-cancer analysis of whole genomes (PCAWG) Project and ~ 60,000 whole-exomes from the Exome Aggregation Consortium (ExAC) database. Of the 28,084,558 CpG sites in the human reference genome, 26.0% show C:G > T:A substitution in the dataset. Remarkably, CpGs in CpG islands (CGIs) have a much lower frequency of such mutations (5.6%). Interestingly, the mutation frequency of CGIs is not uniform with a significantly higher C:G > T:A substitution rate for intragenic CGIs compared to other types. For non-CGI CpGs, the mutation rate was positively correlated with the distance from the nearest CGI up to 2 kb. Finally, we found the impact of negative selection for coding CpG mutations resulting in amino acid change. This study provides the first unbiased rate of C:G > T:A substitution at the CpG dinucleotide contexts, using population-scale human genome sequencing data. Our findings provide insights into the dynamics of the mutation acquisition in the human genome.

中文翻译：

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在人群中CpG环境中C：G> T：A多态性的全基因组景观

CpG二核苷酸上下文中的C：G> T：A取代是基因组进化中最常见的取代类型。突变过程显然是在人类种系中进行的。然而，其对常见和罕见基因组多态性的影响尚未得到全面研究。在这里，我们从人口规模的人类基因组测序数据集中观察了C：G> T：A替代的态势和动态，包括1000个基因组的〜4300个全基因组以及全基因组的泛癌分析（PCAWG）项目和约60,000个来自Exome Aggregation Consortium（ExAC）数据库的全外显子组。在人类参考基因组中的28,084,558个CpG位点中，有26.0％在数据集中显示C：G> T：A取代。值得注意的是，CpG岛（CGI）中的CpG发生此类突变的频率要低得多（5.6％）。有趣的是 与其他类型相比，基因内CGI的C：G> T：A替代率显着更高，因此CGI的突变频率不一致。对于非CGI CpG，突变率与距最近的CGI直至2 kb的距离呈正相关。最后，我们发现了负选择对编码CpG突变导致氨基酸变化的影响。这项研究使用人口规模的人类基因组测序数据，提供了CpG二核苷酸背景下C：G> T：A取代的第一个无偏率。我们的发现为人类基因组突变获取的动力学提供了见识。突变率与距最近的CGI直至2 kb的距离呈正相关。最后，我们发现了负选择对编码CpG突变导致氨基酸变化的影响。这项研究使用人口规模的人类基因组测序数据，提供了CpG二核苷酸背景下C：G> T：A取代的第一个无偏率。我们的发现为人类基因组突变获取的动力学提供了见识。突变率与距最近的CGI直至2 kb的距离呈正相关。最后，我们发现了负选择对编码CpG突变导致氨基酸变化的影响。这项研究使用人口规模的人类基因组测序数据，提供了CpG二核苷酸背景下C：G> T：A取代的第一个无偏率。我们的发现为人类基因组突变获取的动力学提供了见识。