Park Leeyoung
Natural Science Research Institute, Yonsei University, 134 Shinchon-Dong, Seodaemun-Ku, Seoul, Korea.
Genet Res (Camb). 2009 Aug;91(4):293-303. doi: 10.1017/S0016672309990164.
This study aims to comprehensively examine the mutation rates of one base for another in human gene loci. In contrast to most previous efforts based on divergence data from untranscribed regions, the present study employs the basic theory of the reversible recurrent mutation model using large-scale, high-quality re-sequencing data from public databases of gene loci. Population mutation parameters (4Nnu and 4Nmu) are obtained for each pair of base substitutions. The estimated parameters show good strand reversal symmetry, supporting the existence of mutation-drift equilibrium. Analysis of specific gene regions including mRNA, coding sequence (CDS), 5'-untranslated region (5'-UTRs), 3'-UTR and intron shows that there are clear differences in the mutation rates of each base for another depending on the location of the base in question. Results from analyses that take the adjacent bases into account exhibit excellent strand reversal symmetry, confirming that the identity of an adjacent base influences mutation rates. The CpG to TpG (or CpG to CpA) substitution is found at a rate approximately seven-fold higher than the reverse transition in intron regions due to cytosine deamination, but the effect is strongly reduced in mRNA regions and almost entirely lost in 5'-UTRs. However, from the overall increased transitions in sites other than CpGs and the proportion of CpGs in the total sequence, CpG methylation is not the main factor responsible for the increased rate of transitions as compared with transversions. In this report, after adjusting average mutation rates to the sequence compositions, no substitution bias is found between A+T and C+G, indicating base composition equilibrium in human gene loci. Population differences are also identified between groups of people of African and European descent, presumably due to past population histories. By applying the basic theory of population genetics to re-sequenced data, this study contributes new, detailed information regarding mutations in human gene regions.
本研究旨在全面检测人类基因位点中一个碱基突变为另一个碱基的突变率。与以往大多数基于非转录区域分歧数据的研究不同，本研究采用可逆反复突变模型的基本理论，利用来自基因位点公共数据库的大规模、高质量重测序数据。获得了每对碱基替换的群体突变参数（4Nnu和4Nmu）。估计参数显示出良好的链反转对称性，支持突变-漂变平衡的存在。对包括mRNA、编码序列（CDS）、5'-非翻译区（5'-UTR）、3'-UTR和内含子在内的特定基因区域的分析表明，根据所讨论碱基的位置，一个碱基突变为另一个碱基的突变率存在明显差异。考虑相邻碱基的分析结果显示出优异的链反转对称性，证实相邻碱基的身份会影响突变率。由于胞嘧啶脱氨作用，在内含子区域中，CpG到TpG（或CpG到CpA）的替换发生率比反向转换高约7倍，但在mRNA区域中这种效应大大降低，在5'-UTR中几乎完全消失。然而，从除CpG位点以外其他位点总体上增加的转换以及CpG在总序列中的比例来看，与颠换相比，CpG甲基化并非转换率增加的主要原因。在本报告中，将平均突变率调整为序列组成后，未发现A+T和C+G之间存在替换偏差，表明人类基因位点中的碱基组成处于平衡状态。还确定了非洲裔和欧洲裔人群之间的群体差异，这可能是由于过去的群体历史所致。通过将群体遗传学的基本理论应用于重测序数据，本研究为人类基因区域的突变提供了新的详细信息。
