Scientific Institute IRCCS E. MEDEA, Computational Biology Unit, Bosisio Parini 23842, Italy.
Shmunis School of Biomedicine and Cancer Research, George S Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel.
Mol Biol Evol. 2024 Aug 2;41(8). doi: 10.1093/molbev/msae154.
Several mammalian genes have originated from the domestication of retrotransposons, selfish mobile elements related to retroviruses. Some of the proteins encoded by these genes have maintained virus-like features; including self-processing, capsid structure formation, and the generation of different isoforms through -1 programmed ribosomal frameshifting. Using quantitative approaches in molecular evolution and biophysical analyses, we studied 28 retrotransposon-derived genes, with a focus on the evolution of virus-like features. By analyzing the rate of synonymous substitutions, we show that the -1 programmed ribosomal frameshifting mechanism in three of these genes (PEG10, PNMA3, and PNMA5) is conserved across mammals and originates alternative proteins. These genes were targets of positive selection in primates, and one of the positively selected sites affects a B-cell epitope on the spike domain of the PNMA5 capsid, a finding reminiscent of observations in infectious viruses. More generally, we found that retrotransposon-derived proteins vary in their intrinsically disordered region content and this is directly associated with their evolutionary rates. Most positively selected sites in these proteins are located in intrinsically disordered regions and some of them impact protein posttranslational modifications, such as autocleavage and phosphorylation. Detailed analyses of the biophysical properties of intrinsically disordered regions showed that positive selection preferentially targeted regions with lower conformational entropy. Furthermore, positive selection introduces variation in binary sequence patterns across orthologues, as well as in chain compaction. Our results shed light on the evolutionary trajectories of a unique class of mammalian genes and suggest a novel approach to study how intrinsically disordered region biophysical characteristics are affected by evolution.
许多哺乳动物基因来源于逆转录转座子的驯化，即与逆转录病毒相关的自私移动元件。这些基因编码的一些蛋白质保留了病毒样特征，包括自我加工、衣壳结构形成，以及通过 -1 程序性核糖体移码产生不同的同工型。我们使用分子进化和生物物理分析的定量方法研究了 28 个逆转录转座子衍生基因，重点研究了病毒样特征的进化。通过分析同义替换率，我们表明这三个基因（PEG10、PNMA3 和 PNMA5）中的 -1 程序性核糖体移码机制在哺乳动物中是保守的，并产生了替代蛋白。这些基因在灵长类动物中受到正选择，其中一个正选择位点影响了 PNMA5 衣壳的刺突域上的 B 细胞表位，这一发现让人联想到感染性病毒的观察结果。更普遍地说，我们发现逆转录转座子衍生蛋白在其固有无序区含量上存在差异，这与它们的进化速率直接相关。这些蛋白中大多数正选择位点位于固有无序区，其中一些影响蛋白翻译后的修饰，如自切割和磷酸化。对固有无序区生物物理特性的详细分析表明，正选择优先靶向构象熵较低的区域。此外，正选择在同源物之间引入了二进制序列模式的变异，以及链的压缩。我们的研究结果揭示了一类独特的哺乳动物基因的进化轨迹，并提出了一种新的方法来研究固有无序区生物物理特性如何受到进化的影响。
