Walser Jean-Claude, Ponger Loïc, Furano Anthony V
Section on Genomic Structure and Function, Laboratory of Molecular and Cellular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-0830, USA.
Genome Res. 2008 Sep;18(9):1403-14. doi: 10.1101/gr.076455.108. Epub 2008 Jun 11.
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 approximately 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 approximately 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 (R2 = 0.98) correlation for approximately 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.
当碱基替换率不受自然选择影响时，中性突变率与之相等。这些速率之间的差异可能表明自然选择、连锁或突变基因座等因素正在影响特定序列。我们通过测量散布在人类和黑猩猩基因组中的约30000对无活性直系同源L1逆转座子序列的序列差异，来检测中性碱基替换率。与其他研究不同的是，我们将直系同源序列的差异与L1序列在黑猩猩和人类物种形成之前在基因组中存在的时间（年龄）联系起来。正如预期的那样，由于较年轻的直系同源序列中的CpG转变为TpG（和CpA），其所含的高变CpG比老的直系同源序列更多。因此，自人类和黑猩猩谱系分离以来的大约500万年里，较年轻的直系同源序列比老的积累了更多的CpG突变。但在同一时期，较年轻的直系同源序列积累的非CpG突变也比老的多。事实上，对于约97%的直系同源序列对，非CpG和CpG突变显示出几乎完美的相关性（R2 = 0.98）。这种相关性与G + C含量、重组率和染色体位置无关。因此，它可能反映了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。CpG效应在非CpG DNA的所有区域并不一致。因此，非CpG DNA的突变率在不同程度上取决于局部CpG含量。除了对突变机制的影响外，这些结果表明可能无法精确确定全基因组范围内统一的中性突变率。
