Kondrashov Fyodor A, Ogurtsov Aleksey Y, Kondrashov Alexey S
Section of Ecology, Behavior and Evolution, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0346, USA.
J Theor Biol. 2006 Jun 21;240(4):616-26. doi: 10.1016/j.jtbi.2005.10.020. Epub 2005 Dec 15.
The impact of synonymous nucleotide substitutions on fitness in mammals remains controversial. Despite some indications of selective constraint, synonymous sites are often assumed to be neutral, and the rate of their evolution is used as a proxy for mutation rate. We subdivide all sites into four classes in terms of the mutable CpG context, nonCpG, postC, preG, and postCpreG, and compare four-fold synonymous sites and intron sites residing outside transposable elements. The distribution of the rate of evolution across all synonymous sites is trimodal. Rate of evolution at nonCpG synonymous sites, not preceded by C and not followed by G, is approximately 10% below that at such intron sites. In contrast, rate of evolution at postCpreG synonymous sites is approximately 30% above that at such intron sites. Finally, synonymous and intron postC and preG sites evolve at similar rates. The relationship between the levels of polymorphism at the corresponding synonymous and intron sites is very similar to that between their rates of evolution. Within every class, synonymous sites are occupied by G or C much more often than intron sites, whose nucleotide composition is consistent with neutral mutation-drift equilibrium. These patterns suggest that synonymous sites are under weak selection in favor of G and C, with the average coefficient s approximately 0.25/Ne approximately 10(-5), where Ne is the effective population size. Such selection decelerates evolution and reduces variability at sites with symmetric mutation, but has the opposite effects at sites where the favored nucleotides are more mutable. The amino-acid composition of proteins dictates that many synonymous sites are CpGprone, which causes them, on average, to evolve faster and to be more polymorphic than intron sites. An average genotype carries approximately 10(7) suboptimal nucleotides at synonymous sites, implying synergistic epistasis in selection against them.
同义核苷酸替换对哺乳动物适应性的影响仍存在争议。尽管有一些选择性限制的迹象，但同义位点通常被认为是中性的，其进化速率被用作突变率的替代指标。我们根据可变的CpG上下文将所有位点细分为四类，即非CpG、C后、G前和C后G前，并比较四倍同义位点和位于转座元件之外的内含子位点。所有同义位点的进化速率分布呈三峰型。在非CpG同义位点（即前面不是C且后面不是G的位点）的进化速率比此类内含子位点低约10%。相反，C后G前同义位点的进化速率比此类内含子位点高约30%。最后，同义位点以及内含子的C后和G前位点以相似的速率进化。相应同义位点和内含子位点的多态性水平之间的关系与它们的进化速率之间的关系非常相似。在每一类中，同义位点被G或C占据的频率比内含子位点高得多，内含子位点的核苷酸组成与中性突变 - 漂变平衡一致。这些模式表明同义位点受到有利于G和C的弱选择，平均选择系数s约为0.25/Ne≈10⁻⁵，其中Ne是有效种群大小。这种选择减缓了进化并降低了对称突变位点的变异性，但在有利核苷酸更易突变的位点则产生相反的效果。蛋白质的氨基酸组成决定了许多同义位点易于发生CpG突变，这导致它们平均比内含子位点进化得更快且多态性更高。一个平均基因型在同义位点携带约10⁷个次优核苷酸，这意味着在针对它们的选择中存在协同上位性。
