Evolutionary Forces and Codon Bias in Different Flavors of Intrinsic Disorder in the Human Proteome
Evolutionary Forces and Codon Bias in Different Flavors of Intrinsic Disorder in the Human Proteome
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DOI：
10.1007/s00239-019-09921-4
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发表时间：
2020-03-01
影响因子：
3.9
通讯作者：
Giansanti, Andrea
中科院分区：
文献类型：
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作者：
Forcelloni, Sergio;Giansanti, Andrea
在这项研究中，我们对进化力量(即突变偏向和自然选择)进行了系统的分析，这些力量塑造了编码具有不同内在紊乱特征的蛋白质的人类基因的密码子使用偏向。通过净化自然选择，结构良好的蛋白质预计会比内在无序的蛋白质更容易受到控制，因为基因中的一个或几个突变(甚至是同义词)可能导致蛋白质不再正确折叠。相反，由于宽松的净化自然选择和突变偏向的作用增加，内在无序的蛋白质被认为比折叠良好的蛋白质进化得更快。使用不同的生物信息学工具，我们发现证据表明，密码子在IDPs中的使用不仅受到基本的突变偏见的影响，而且比人类蛋白质组的其余部分更有选择性地受到限制。我们推测，本质上无序的蛋白质不仅对突变有很高的耐受性，而且有选择性地倾向于在生理条件下保留其结构无序。此外，我们证实，不仅内在无序的蛋白质优先由富含GC的基因编码，而且它们的特征是序列中最高比例的CpG位点，这意味着更容易发生甲基化导致C-T转换突变。总体而言，我们的结果证实了内在紊乱对蛋白质进化适应性和进化性的重要作用，不仅从功能属性和在疾病中的作用而且从它们所受的进化力方面为蛋白质进化提供了新的见解。
In this study, we perform a systematic analysis of evolutionary forces (i.e., mutational bias and natural selection) that shape the codon usage bias of human genes encoding proteins characterized by different flavors of intrinsic disorder. Well-structured proteins are expected to be more under control by purifying natural selection than intrinsically disordered proteins because one or few mutations (even synonymous) in the genes can result in a protein that no longer folds correctly. On the contrary, intrinsically disordered proteins are thought to evolve more rapidly than well-folded proteins, due to a relaxed purifying natural selection and an increased role of mutational bias. Using different bioinformatic tools, we find evidence that codon usage in IDPs is not only affected by a basic mutational bias, but it is also more selectively constrained than the rest of the human proteome. We speculate that intrinsically disordered proteins have not only a high tolerance to mutations but also a selective propensity to preserve their structural disorder under physiological conditions. Additionally, we confirm not only that intrinsically disordered proteins are preferentially encoded by GC-rich genes, but also that they are characterized by the highest fraction of CpG sites in the sequences, implying a higher susceptibility to methylation resulting in C-T transition mutations. Overall, our results corroborate the essential role of intrinsic disorder for the evolutionary adaptability and evolvability of proteins, offering new insight about protein evolution not only in terms of functional properties and roles in diseases but also in terms of evolutionary forces they are subjected to.