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首页> 外文期刊>BMC Genomics >Modelling mutational and selection pressures on dinucleotides in eukaryotic phyla –selection against CpG and UpA in cytoplasmically expressed RNA and in RNA viruses
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Modelling mutational and selection pressures on dinucleotides in eukaryotic phyla –selection against CpG and UpA in cytoplasmically expressed RNA and in RNA viruses

机译：模拟真核生物门中二核苷酸的突变和选择压力-在细胞质表达的RNA和RNA病毒中针对CpG和UpA的选择

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Background Loss of CpG dinucleotides in genomic DNA through methylation-induced mutation is characteristic of vertebrates and plants. However, these and other eukaryotic phyla show a range of other dinucleotide frequency biases with currently uncharacterized underlying mutational or selection mechanisms. We developed a parameterized Markov process to identify what neighbour context-dependent mutations best accounted for patterns of dinucleotide frequency biases in genomic and cytoplasmically expressed mRNA sequences of different vertebrates, other eukaryotic groups and RNA viruses that infect them. Results Consistently, 11- to 14-fold greater frequencies of the methylation-associated mutation of C to T upstream of G (depicted as C→T,G) than other transitions best modelled dinucleotide frequencies in mammalian genomic DNA. However, further mutations such as G→T,T (5-fold greater than the default transversion rate) were required to account for the full spectrum of dinucleotide frequencies in mammalian sequence datasets. Consistent with modeling predictions for these two mutations, instability of both CpG and CpT dinucleotides was identified through SNP frequency analysis of human DNA sequences. Different sets of context-dependent mutations were modelled in other eukaryotes with non-methylated genomic DNA. In contrast to genomic DNA, best-fit models of dinucleotide frequencies in transcribed RNA sequences expressed in the cytoplasm from all organisms were dominated by mutations that eliminated UpA dinucleotides, observations consistent with cytoplasmically driven selection for mRNA stability. Surprisingly, mRNA sequences from organisms with methylated genomes showed evidence for additional selection against CpG through further context-dependent mutations (eg. C→A,G). Similar mutation or selection processes were identified among single-stranded mammalian RNA viruses; these potentially account for their previously described but unexplained under-representations of CpG and UpA dinucleotides. Conclusions Methods we have developed identify mutational processes and selection pressures in organisms that provide new insights into nucleotide compositional constraints and a wealth of biochemical and evolutionarily testable predictions for the future.
机译：背景通过甲基化诱导的突变，基因组DNA中CpG二核苷酸的丢失是脊椎动物和植物的特征。但是，这些和其他真核生物门表现出一系列其他二核苷酸频率偏倚，具有目前未知的潜在突变或选择机制。我们开发了一个参数化的马尔可夫过程，以确定哪些邻域背景相关的突变最能解释不同脊椎动物，其他真核生物组和感染它们的基因组和细胞质表达的mRNA序列中双核苷酸频率偏向的模式。结果一致地，与哺乳动物基因组DNA中最佳模拟的其他二核苷酸频率相比，C到G上游的T的甲基化相关突变（从C→T，G表示）的频率高出11至14倍。但是，还需要进一步的突变，例如G→T，T（比默认转化率大5倍），才能说明哺乳动物序列数据集中双核苷酸频率的全谱。与这两个突变的建模预测一致，通过对人类DNA序列的SNP频率分析确定了CpG和CpT二核苷酸的不稳定性。使用非甲基化的基因组DNA在其他真核生物中模拟了不同背景依赖的突变集。与基因组DNA相反，所有生物体在细胞质中表达的转录RNA序列中最合适的双核苷酸频率模型是由消除UpA双核苷酸的突变所决定的，这一观察结果与细胞质驱动的mRNA稳定性选择相符。出乎意料的是，来自具有甲基化基因组的生物的mRNA序列显示出通过进一步的背景依赖性突变（例如C→A，G）针对CpG进行额外选择的证据。在单链哺乳动物RNA病毒中发现了相似的突变或选择过程。这些可能解释了它们先前描述的CpG和UpA二核苷酸的不足，但无法解释。结论我们已经开发出的方法可以识别生物体中的突变过程和选择压力，从而为核苷酸组成限制以及对未来的大量生化和可进化检验的预测提供新的见解。

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