Differential requirements for mRNA folding partially explain why highly expressed proteins evolve slowly
Differential requirements for mRNA folding partially explain why highly expressed proteins evolve slowly
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DOI：
10.1073/pnas.1218066110
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发表时间：
2013-02-19
影响因子：
11.1
通讯作者：
Zhang, Jianzhi
中科院分区：
文献类型：
--
作者：
Park, Chungoo;Chen, Xiaoshu;Zhang, Jianzhi
蛋白质间序列进化速度差异巨大的原因是分子进化的中心课题。表达水平已被确定为同一基因组中编码基因差异的主要决定因素，但其潜在机制尚不完全清楚。我们在此提出并证明，对更丰富的mrna的更强折叠的要求导致更高表达的基因和蛋白质的进化更慢。具体来说，我们表明：(i)基因的表达水平越高，其mRNA折叠的选择压力越大；（ii）随机突变在高表达基因中比在低表达基因中更有可能减少mRNA折叠；（iii）氨基酸取代率与mRNA折叠强度负相关，无论是否控制表达水平。此外，同义（d(S)）和非同义（d(N)）核苷酸取代率都与mRNA折叠强度呈负相关。然而，与直觉相反，d(S)和d(N)受到mRNA折叠选择的差异约束，导致mRNA折叠强度与d(N)/d(S)之间存在显著相关性，即使在基因表达水平受控的情况下也是如此。这种相关性的方向和大小主要由第三个密码子位置的G+C频率决定。总之，这些发现解释了为什么高表达基因进化缓慢，证明了mRNA水平的自然选择在限制蛋白质进化中的主要作用，并揭示了一种以前未被认识和意想不到的影响d(N)/d(S)的非蛋白质水平选择形式。
The cause of the tremendous among-protein variation in the rate of sequence evolution is a central subject of molecular evolution. Expression level has been identified as a leading determinant of this variation among genes encoded in the same genome, but the underlying mechanisms are not fully understood. We here propose and demonstrate that a requirement for stronger folding of more abundant mRNAs results in slower evolution of more highly expressed genes and proteins. Specifically, we show that: (i) the higher the expression level of a gene, the greater the selective pressure for its mRNA to fold; (ii) random mutations are more likely to decrease mRNA folding when occurring in highly expressed genes than in lowly expressed genes; and (iii) amino acid substitution rate is negatively correlated with mRNA folding strength, with or without the control of expression level. Furthermore, synonymous (d(S)) and nonsynonymous (d(N)) nucleotide substitution rates are both negatively correlated with mRNA folding strength. However, counterintuitively, d(S) and d(N) are differentially constrained by selection for mRNA folding, resulting in a significant correlation between mRNA folding strength and d(N)/d(S), even when gene expression level is controlled. The direction and magnitude of this correlation is determined primarily by the G+C frequency at third codon positions. Together, these findings explain why highly expressed genes evolve slowly, demonstrate a major role of natural selection at the mRNA level in constraining protein evolution, and reveal a previously unrecognized and unexpected form of nonprotein-level selection that impacts d(N)/d(S).