CpG dinucleotides and the mutation rate of non-CpG DNA
CpG dinucleotides and the mutation rate of non-CpG DNA
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DOI：
10.1101/gr.076455.108
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发表时间：
2008-09-01
期刊：
影响因子：
7
通讯作者：
Furano, Anthony V.
中科院分区：
文献类型：
--
作者：
Walser, Jean-Claude;Ponger, Loic;Furano, Anthony V.
当碱基取代率不受自然选择影响时，中性突变率等于碱基取代率。这些比率之间的差异可能表明自然选择、连锁或突变位点等因素正在影响给定的序列。我们通过测量散布在人类和黑猩猩基因组中的近30,000对无活性的同源L1反转录转座子序列的序列差异来检测中性碱基取代率。与其他研究相反，我们将直系同源分化与L1序列在黑猩猩和人类物种形成之前驻留在基因组中的时间（年龄）联系起来。正如预期的那样，较年轻的同源物比较老的同源物含有更多的超可变cpg，因为它们转化为TpGs（和CpAs）。因此，在人类和黑猩猩谱系分离后大约500万年的时间里，较年轻的同源基因比较年长的同源基因积累了更多的CpG突变。但在同一时期，年轻的同源基因也比年长的基因积累了更多的非cpg突变。事实上，在97%的同源基因对中，非CpG和CpG突变表现出几乎完美的相关性（R-2 = 0.98）。相关性与G + C含量、重组率和染色体位置无关。因此，这可能反映了cpg或其突变对非cpg DNA的内在影响，而不是染色体环境的共同表现。对于非CpG DNA的所有区域，CpG效应并不均匀。因此，非CpG DNA的突变率在不同程度上取决于局部CpG含量。除了它们对突变机制的影响外，这些结果表明，精确确定统一的全基因组中性突变率可能是无法实现的。
The neutral mutation rate is equal to the base substitution rate when the latter is not affected by natural selection. Differences between these rates may reveal that factors such as natural selection, linkage, or a mutator locus are affecting a given sequence. We examined the neutral base substitution rate by measuring the sequence divergence of similar to 30,000 pairs of inactive orthologous L1 retrotransposon sequences interspersed throughout the human and chimpanzee genomes. In contrast to other studies, we related ortholog divergence to the time ( age) that the L1 sequences resided in the genome prior to the chimpanzee and human speciation. As expected, the younger orthologs contained more hypermutable CpGs than the older ones because of their conversion to TpGs (and CpAs). Consequently, the younger orthologs accumulated more CpG mutations than the older ones during the similar to 5 million years since the human and chimpanzee lineages separated. But during this same time, the younger orthologs also accumulated more non-CpG mutations than the older ones. In fact, non-CpG and CpG mutations showed an almost perfect (R-2 = 0.98) correlation for similar to 97% of the ortholog pairs. The correlation is independent of G + C content, recombination rate, and chromosomal location. Therefore, it likely reflects an intrinsic effect of CpGs, or mutations thereof, on non-CpG DNA rather than the joint manifestation of the chromosomal environment. The CpG effect is not uniform for all regions of non-CpG DNA. Therefore, the mutation rate of non-CpG DNA is contingent to varying extents on local CpG content. Aside from their implications for mutational mechanisms, these results indicate that a precise determination of a uniform genome-wide neutral mutation rate may not be attainable.