Pirovino Magnus, Iseli Christian, Curran Joseph A, Conrad Bernard
OPIRO Consulting Ltd., Triesen, Principality of Liechtenstein.
Bioinformatics Competence Center, EPFL and Unil, Lausanne, Switzerland.
PLoS Comput Biol. 2025 Jan 3;21(1):e1012162. doi: 10.1371/journal.pcbi.1012162. eCollection 2025 Jan.
Catalysis and specifically autocatalysis are the quintessential building blocks of life. Yet, although autocatalytic networks are necessary, they are not sufficient for the emergence of life-like properties, such as replication and adaptation. The ultimate and potentially fatal threat faced by molecular replicators is parasitism; if the polymerase error rate exceeds a critical threshold, even the fittest molecular species will disappear. Here we have developed an autocatalytic RNA early life mathematical network model based on enzyme kinetics, specifically the steady-state approximation. We confirm previous models showing that these second-order autocatalytic cycles are sustainable, provided there is a sufficient nucleotide pool. However, molecular parasites become untenable unless they sequentially degenerate to hyperparasites (i.e. parasites of parasites). Parasite resistance-a parasite-specific host response decreasing parasite fitness-is acquired gradually, and eventually involves an increased binding affinity of hyperparasites for parasites. Our model is supported at three levels; firstly, ribozyme polymerases display Michaelis-Menten saturation kinetics and comply with the steady-state approximation. Secondly, ribozyme polymerases are capable of sustainable auto-amplification and of surmounting the fatal error threshold. Thirdly, with growing sequence divergence of host and parasite catalysts, the probability of self-binding is expected to increase and the trend towards cross-reactivity to diminish. Our model predicts that primordial host-RNA populations evolved via an arms race towards a host-parasite-hyperparasite catalyst trio that conferred parasite resistance within an RNA replicator niche. While molecular parasites have traditionally been viewed as a nuisance, our model argues for their integration into the host habitat rather than their separation. It adds another mechanism-with biochemical precision-by which parasitism can be tamed and offers an attractive explanation for the universal coexistence of catalyst trios within prokaryotes and the virosphere, heralding the birth of a primitive molecular immunity.
催化作用，特别是自催化作用，是生命的典型构成要素。然而，尽管自催化网络是必要的，但它们并不足以产生诸如复制和适应等类似生命的特性。分子复制体面临的最终且可能致命的威胁是寄生现象；如果聚合酶错误率超过临界阈值，即使是最适应环境的分子物种也会消失。在此，我们基于酶动力学，特别是稳态近似法，开发了一个自催化RNA早期生命数学网络模型。我们证实了先前的模型，即只要有足够的核苷酸库，这些二阶自催化循环就是可持续的。然而，分子寄生虫变得难以维持，除非它们依次退化为超级寄生虫（即寄生虫的寄生虫）。寄生虫抗性——一种降低寄生虫适应性的寄生虫特异性宿主反应——是逐渐获得的，最终涉及超级寄生虫对寄生虫结合亲和力的增加。我们的模型在三个层面得到支持：首先，核酶聚合酶表现出米氏饱和动力学，并符合稳态近似法。其次，核酶聚合酶能够进行可持续的自我扩增，并能跨越致命的错误阈值。第三，随着宿主和寄生虫催化剂序列差异的增加，自我结合的概率预计会增加，交叉反应的趋势会减弱。我们的模型预测，原始宿主RNA群体通过军备竞赛进化为宿主 - 寄生虫 - 超级寄生虫催化剂三元组，该三元组在RNA复制体生态位内赋予寄生虫抗性。虽然分子寄生虫传统上被视为一种麻烦，但我们的模型主张将它们整合到宿主栖息地中，而不是将它们分离。它增加了另一种具有生化精确性的机制，通过这种机制可以控制寄生现象，并为原核生物和病毒圈中催化剂三元组的普遍共存提供了一个有吸引力的解释，预示着原始分子免疫的诞生。
