Abstract：
Protein coding genes terminate with one of three stop codons (TAA, TGA, or TAG) that, like synonymous codons, are not employed equally. With TGA and TAG having identical nucleotide content, analysis of their differential usage provides an unusual window into the forces operating on what are ostensibly functionally identical residues. Across genomes and between isochores within the human genome, TGA usage increases with G + C content but, with a common G + C → A + T mutation bias, this cannot be explained by mutation bias-drift equilibrium. Increased usage of TGA in G + C-rich genomes or genomic regions is also unlikely to reflect selection for the optimal stop codon, as TAA appears to be universally optimal, probably because it has the lowest read-through rate. Despite TAA being favored by selection and mutation bias, as with codon usage bias G + C pressure is the prime determinant of between-species TGA usage trends. In species with strong G + C-biased gene conversion (gBGC), such as mammals and birds, the high usage and conservation of TGA is best explained by an A + T → G + C repair bias. How to explain TGA enrichment in other G + C-rich genomes is less clear. Enigmatically, across bacterial and archaeal species and between human isochores TAG usage is mostly unresponsive to G + C pressure. This unresponsiveness we dub the TAG paradox as currently no mutational, selective, or gBGC model provides a well-supported explanation. That TAG does increase with G + C usage across eukaryotes makes the usage elsewhere yet more enigmatic. We suggest resolution of the TAG paradox may provide insights into either an unknown but common selective preference (probably at the DNA/RNA level) or an unrecognized complexity to the action of gBGC.
摘要：
蛋白质编码基因以三个终止密码子之一终止(TAA，TGA,或标签)，就像同义词一样，没有平等的就业。TGA和TAG具有相同的核苷酸含量，对其差异用法的分析提供了一个不寻常的窗口，以了解表面上功能相同的残留物的作用力。跨基因组和人类基因组内的等值序列之间，TGA的使用随着G+C含量的增加而增加，但是，具有常见的G+C→A+T突变偏差，这不能用突变偏差-漂移平衡来解释。在富含G+C的基因组或基因组区域中增加TGA的使用也不太可能反映对最佳终止密码子的选择。由于TAA似乎是普遍最优的，可能是因为它的通读率最低。尽管TAA受到选择和突变偏倚的青睐，与密码子使用偏好一样，GC压力是物种间TGA使用趋势的主要决定因素。在具有强G+C偏向基因转换（gBGC）的物种中，比如哺乳动物和鸟类，TGA的高使用率和高保守性最好用A+T→G+C修复偏差来解释。如何解释TGA在其他富含G+C的基因组中的富集尚不清楚。神秘,在细菌和古细菌物种之间以及在人类等值机之间，TAG的使用大多对GC压力无反应。这种反应迟钝，我们将TAG悖论称为目前没有突变，选择性,或gBGC模型提供了一个支持良好的解释。该TAG确实随着GC在真核生物中的使用而增加，这使其他地方的使用更加神秘。我们建议解决TAG悖论可以提供对未知但常见的选择性偏好（可能在DNA/RNA水平上）或对gBGC作用的未知复杂性的见解。
