Species from Hidden patterns of codon usage bias across kingdoms

The genetic code is necessarily degenerate with 64 possible nucleotide triplets being translated into 20 amino acids. 18 out of the 20 amino acids are encoded by multiple synonymous codons. While synonymous codons are clearly equivalent in terms of the information they carry, it is now well established that they are used in a biased fashion. There is currently no consensus as to the origin of this bias. Drawing on ideas from stochastic thermodynamics we derive from first principles a mathematical model describing the statistics of codon usage bias. We show that the model accurately describes the distribution of codon usage bias of genomes in the fungal and bacterial kingdoms. Based on it, we derive a new computational measure of codon usage bias—the distance D capturing two aspects of codon usage bias: (i) Differences in the genome-wide frequency of codons and (ii) apparent non-random distributions of codons across mRNAs. By means of large scale computational analysis of over 900 species across two kingdoms of life, we demonstrate that our measure provides novel biological insights. Specifically, we show that while codon usage bias is clearly based on heritable traits and closely related species show similar degrees of bias, there is considerable variation in the magnitude of D within taxonomic classes suggesting that the contribution of sequence-level selection to codon bias varies substantially within relatively confined taxonomic groups. Interestingly, commonly used model organisms are near the median for values of D for their taxonomic class, suggesting that they may not be good representative models for species with more extreme D, which comprise organisms of medical an agricultural interest. We also demonstrate that amino acid specific patterns of codon usage are themselves quite variable between branches of the tree of life, and that some of this variability correlates with organismal tRNA content.

遗传密码（genetic code）必然具有简并性：64种可能的核苷酸三联体可被翻译为20种氨基酸。20种氨基酸中有18种可由多个同义密码子（synonymous codon）编码。尽管同义密码子所携带的遗传信息完全等价，但学界现已公认，密码子的使用存在偏倚现象。目前学界对该偏倚的起源尚未达成共识。本研究借鉴随机热力学（stochastic thermodynamics）的相关理念，从第一性原理出发推导得到一个描述密码子使用偏倚统计特征的数学模型。研究表明，该模型可精准拟合真菌界与细菌界基因组的密码子使用偏倚分布特征。基于该模型，本研究推导得到一种全新的密码子使用偏倚量化计算指标——距离D，该指标可涵盖密码子使用偏倚的两个核心维度：(i) 全基因组范围内密码子频率的差异；(ii) 密码子在信使RNA（mRNA）上的非随机分布特征。本研究通过对两个生物界共900余个物种开展大规模计算分析，证实该指标可提供全新的生物学视角。具体而言，尽管密码子使用偏倚显然由可遗传性状决定，且亲缘关系较近的物种其偏倚程度相近，但在同一分类纲内，距离D的数值仍存在显著差异——这表明序列水平选择对密码子偏倚的贡献度，在相对狭窄的分类类群内仍存在显著波动。值得注意的是，常用模式生物在其所属分类纲的距离D数值中均处于中位数附近，这意味着它们或许无法很好地代表那些具有极端D值的物种，而这类物种往往兼具医学与农业研究价值。此外，本研究还证实，针对特定氨基酸的密码子使用模式在生命之树的不同分支间存在显著差异，且其中部分差异与生物体的转运RNA（tRNA）含量相关。