Department of Biomolecular Engineering, University of California, Santa Cruz, CA 95064.
Department of Biomolecular Engineering, University of California, Santa Cruz, CA 95064;
Proc Natl Acad Sci U S A. 2018 Sep 4;115(36):8996-9001. doi: 10.1073/pnas.1801240115. Epub 2018 Aug 20.
Transfer RNAs (tRNAs) are a central component for the biological synthesis of proteins, and they are among the most highly conserved and frequently transcribed genes in all living things. Despite their clear significance for fundamental cellular processes, the forces governing tRNA evolution are poorly understood. We present evidence that transcription-associated mutagenesis and strong purifying selection are key determinants of patterns of sequence variation within and surrounding tRNA genes in humans and diverse model organisms. Remarkably, the mutation rate at broadly expressed cytosolic tRNA loci is likely between 7 and 10 times greater than the nuclear genome average. Furthermore, evolutionary analyses provide strong evidence that tRNA genes, but not their flanking sequences, experience strong purifying selection acting against this elevated mutation rate. We also find a strong correlation between tRNA expression levels and the mutation rates in their immediate flanking regions, suggesting a simple method for estimating individual tRNA gene activity. Collectively, this study illuminates the extreme competing forces in tRNA gene evolution and indicates that mutations at tRNA loci contribute disproportionately to mutational load and have unexplored fitness consequences in human populations.
转移 RNA（tRNA）是蛋白质生物合成的核心组成部分，它们是所有生物中最保守和转录频率最高的基因之一。尽管它们对基本细胞过程具有明显的重要性，但控制 tRNA 进化的力量还了解甚少。我们提供的证据表明，转录相关的诱变和强烈的纯化选择是人类和各种模式生物中 tRNA 基因内部和周围序列变异模式的关键决定因素。值得注意的是，广泛表达的细胞质 tRNA 基因座的突变率可能比核基因组平均值高 7 到 10 倍。此外，进化分析提供了强有力的证据，表明 tRNA 基因，而不是其侧翼序列，受到强烈的纯化选择，以对抗这种升高的突变率。我们还发现 tRNA 表达水平与其侧翼区域的突变率之间存在很强的相关性，这表明了一种估计单个 tRNA 基因活性的简单方法。总的来说，这项研究阐明了 tRNA 基因进化中的极端竞争力量，并表明 tRNA 基因座的突变不成比例地增加了突变负荷，并对人类群体的适应性产生了尚未探索的影响。
