Department of Biology and Biochemistry, The Milner Centre for Evolution, University of Bath, United Kingdom.
Genome Biol Evol. 2018 Apr 1;10(4):1153-1173. doi: 10.1093/gbe/evy075.
Stop codons are frequently selected for beyond their regular termination function for error control. The "ambush hypothesis" proposes out-of-frame stop codons (OSCs) terminating frameshifted translations are selected for. Although early indirect evidence was partially supportive, recent evidence suggests OSC frequencies are not exceptional when considering underlying nucleotide content. However, prior null tests fail to control amino acid/codon usages or possible local mutational biases. We therefore return to the issue using bacterial genomes, considering several tests defining and testing against a null. We employ simulation approaches preserving amino acid order but shuffling synonymous codons or preserving codons while shuffling amino acid order. Additionally, we compare codon usage in amino acid pairs, where one codon can but the next, otherwise identical codon, cannot encode an OSC. OSC frequencies exceed expectations typically in AT-rich genomes, the +1 frame and for TGA/TAA but not TAG. With this complex evidence, simply rejecting or accepting the ambush hypothesis is not warranted. We propose a refined post hoc model, whereby AT-rich genomes have more accidental frameshifts, handled by RF2-RF3 complexes (associated with TGA/TAA) and are mostly +1 (or -2) slips. Supporting this, excesses positively correlate with in silico predicted frameshift probabilities. Thus, we propose a more viable framework, whereby genomes broadly adopt one of the two strategies to combat frameshifts: preventing frameshifting (GC-rich) or permitting frameshifts but minimizing impacts when most are caught early (AT-rich). Our refined framework holds promise yet some features, such as the bias of out-of-frame sense codons, remain unexplained.
终止密码子通常在常规终止功能之外被选择用于错误控制。“伏击假说”提出，框架移位翻译的无义终止密码子（OSC）被选择。尽管早期的间接证据部分支持了该假说，但最近的证据表明，考虑到潜在的核苷酸含量，OSC 的频率并不异常。然而，之前的无效测试未能控制氨基酸/密码子的使用或可能的局部突变偏差。因此，我们使用细菌基因组重新研究了这个问题，考虑了几种定义和测试无效的测试。我们采用了模拟方法，在保留氨基酸顺序的同时打乱同义密码子，或在打乱密码子的同时保留氨基酸顺序。此外，我们比较了氨基酸对中的密码子使用情况，其中一个密码子可以但下一个相同的密码子不能编码 OSC。OSC 的频率通常在富含 AT 的基因组、+1 框和 TGA/TAA 中超过预期，但在 TAG 中没有。有了这些复杂的证据，简单地接受或拒绝伏击假说都是没有道理的。我们提出了一个经过修正的事后模型，即在富含 AT 的基因组中，更多的偶然框架移位是由 RF2-RF3 复合物（与 TGA/TAA 相关）处理的，并且大多数是+1（或-2）滑动。支持这一点的是，过剩与计算机预测的框架移位概率呈正相关。因此，我们提出了一个更可行的框架，即基因组广泛采用两种策略中的一种来对抗框架移位：防止框架移位（富含 GC）或允许框架移位，但在大多数早期被捕获时最小化影响（富含 AT）。我们的修正框架有希望，但仍有一些特征，如无义 sense 密码子的偏差，尚未得到解释。
