Genome Science and Technology, University of Tennessee, Knoxville, United States.
Current Address: Department of Genetics, Rutgers University, Piscataway, United States.
BMC Genomics. 2022 May 30;23(1):408. doi: 10.1186/s12864-022-08635-0.
Codon usage bias (CUB), the non-uniform usage of synonymous codons, occurs across all domains of life. Adaptive CUB is hypothesized to result from various selective pressures, including selection for efficient ribosome elongation, accurate translation, mRNA secondary structure, and/or protein folding. Given the critical link between protein folding and protein function, numerous studies have analyzed the relationship between codon usage and protein structure. The results from these studies have often been contradictory, likely reflecting the differing methods used for measuring codon usage and the failure to appropriately control for confounding factors, such as differences in amino acid usage between protein structures and changes in the frequency of different structures with gene expression.
Here we take an explicit population genetics approach to quantify codon-specific shifts in natural selection related to protein structure in S. cerevisiae and E. coli. Unlike other metrics of codon usage, our approach explicitly separates the effects of natural selection, scaled by gene expression, and mutation bias while naturally accounting for a region's amino acid usage. Bayesian model comparisons suggest selection on codon usage varies only slightly between helix, sheet, and coil secondary structures and, similarly, between structured and intrinsically-disordered regions. Similarly, in contrast to prevous findings, we find selection on codon usage only varies slightly at the termini of helices in E. coli. Using simulated data, we show this previous work indicating "non-optimal" codons are enriched at the beginning of helices in S. cerevisiae was due to failure to control for various confounding factors (e.g. amino acid biases, gene expression, etc.), and rather than selection to modulate cotranslational folding.
Our results reveal a weak relationship between codon usage and protein structure, indicating that differences in selection on codon usage between structures are slight. In addition to the magnitude of differences in selection between protein structures being slight, the observed shifts appear to be idiosyncratic and largely codon-specific rather than systematic reversals in the nature of selection. Overall, our work demonstrates the statistical power and benefits of studying selective shifts on codon usage or other genomic features from an explicitly evolutionary approach. Limitations of this approach and future potential research avenues are discussed.
密码子使用偏性（CUB），即同义密码子的非均匀使用，存在于所有生命领域。适应性 CUB 被假设是由各种选择压力引起的，包括选择有效的核糖体延伸、准确翻译、mRNA 二级结构和/或蛋白质折叠。鉴于蛋白质折叠与蛋白质功能之间的关键联系，许多研究分析了密码子使用与蛋白质结构之间的关系。这些研究的结果往往相互矛盾，这可能反映了用于测量密码子使用的不同方法，以及未能适当控制混淆因素，如蛋白质结构之间的氨基酸使用差异和基因表达时不同结构频率的变化。
在这里，我们采用明确的种群遗传学方法来量化与 S. cerevisiae 和 E. coli 中蛋白质结构相关的自然选择对密码子特异性的影响。与其他密码子使用度量标准不同，我们的方法明确分离了由基因表达放大的自然选择效应和突变偏倚，同时自然考虑了一个区域的氨基酸使用。贝叶斯模型比较表明，在螺旋、片层和线圈二级结构之间，以及在结构域和固有无序区域之间，密码子使用的选择变化很小。同样，与之前的发现相反，我们发现 E. coli 中螺旋末端的密码子使用选择变化很小。使用模拟数据，我们表明之前的研究表明“非最优”密码子在 S. cerevisiae 中螺旋的起始处富集，这是由于未能控制各种混淆因素（例如氨基酸偏倚、基因表达等），而不是选择来调节共翻译折叠。
我们的结果揭示了密码子使用与蛋白质结构之间的弱关系，表明结构之间密码子使用选择的差异很小。除了结构之间选择差异的幅度很小之外，观察到的变化似乎是特殊的，并且主要是密码子特异性的，而不是选择性质的系统反转。总的来说，我们的工作表明，从明确的进化角度研究密码子使用或其他基因组特征的选择变化具有统计优势和好处。讨论了该方法的局限性和未来的潜在研究途径。
