Biology subjects

Mizuuchi, R.

Publications and source records attributed to Mizuuchi, R..

7 recordsLinked to original sources

bioRxiv2026

Molecular communication enables cooperative genomic RNA replication in all-aqueous droplet colonies

Multicellular organization enables biological functions to be distributed among specialized cells and coordinated through intercellular communication. Integrating this organizational principle with genome replication would link functional division of labor to the propagation of genetic information. Here, we show that genomic RNAs with complementary functions can cooperatively replicate across communicating artificial compartments. We constructed multicell-like colonies from all-aqueous droplets formed by phase separation of two incompatible polymers and stabilized at their interfaces by liposomes and amyloid-like proteins. The droplets assembled spontaneously while remaining permeable to protein-sized macromolecules. Two genomic RNAs encoding a replication enzyme and a metabolic enzyme were distributed in distinct colony-forming droplets and cooperatively replicated through cell-free translation and reciprocal molecular communication. These findings establish that genome replication can be collectively supported by communicating artificial compartments and provide a route toward multicell-like systems that coordinate spatially distributed genetic functions.

synthetic biology↗

bioRxiv2026

Emergent primordial heritability in short random RNA pools

The emergence of heritable molecular information is a fundamental step in the origins of life. Prior to the evolution of defined self-reproducing RNAs in the RNA world hypothesis, mixtures of primordial oligonucleotides may have supported more rudimentary forms of information propagation at the population level. To explore this possibility, we investigated the long-term dynamics of fully random short RNA pools under serial transfer conditions. Across multiple populations undergoing iterative nonenzymatic recombination and ligation, overall sequence compositions changed dynamically; however, sequence and structural traits emerged and exhibited modest yet detectable persistence, indicative of a primordial form of heritability. These traits were largely associated with terminal RNA regions, which tend to be unstructured and accessible for subsequent templating reactions, consistent with the enrichment of complementary sequences. The role of complementarity in shaping sequence composition was further confirmed using designed RNAs. Together, these results suggest that fully random RNA mixtures can exhibit a measurable, albeit weak, capacity to propagate newly generated information in the absence of enzymes, potentially representing an early step toward the emergence of genetic systems.

biochemistry↗

bioRxiv2026

Compositional memory matters for early molecular systems

The error catastrophe refers to the proliferation of non-functional molecules in conditions where molecular replication has low accuracy, which is likely to correspond to conditions present at the Origin of Life. This error catastrophe can be avoided thanks to transient compartmentalization, provided that the compartments are sufficiently tight to prevent molecular leakage. Typically, transient compartmentalization models assume that the content of the compartments is completely pooled periodically, resulting in the complete loss of the compositional memory of the compartment. Furthermore, previous models that include the possibility of ecological interactions between molecular parasites and replicators within compartments generally do not study the effect of transient compartmentalization on their coevolution. To address both issues, we develop a framework that accounts for the coevolution of molecular replicators and parasites, along with specific compartmentalization dynamics that are transient yet partial, allowing compositional memory to accumulate from one round of compartmentalization to the next. We benchmark our model with a serial dilution experiment that displays complex oscillatory dynamics among four well-characterized RNA replicators. We also perform experiments to quantify the level of mixing in compartments when stronger stirring tends to homogenize their composition. We then model stirring-induced mixing and show how stirring alters the dynamics of compartmentalized replicators. We conclude that compositional memory arising from transient compartmentalization plays a major role in the dynamics of early molecular systems.

biophysics↗

bioRxiv2025

Experimental evolution toward extinction in a molecular host-parasite system

Theoretical studies have proposed that coevolution with parasitic replicators plays a critical role in the evolution of primitive life; however, experimental verification of the potential outcomes of such coevolutionary dynamics remains limited. We previously conducted a co-evolutionary experiment using an RNA-protein replication system that resulted in the spontaneous diversification of host and parasitic RNAs into five distinct lineages with robust co-replication. Here, we report contrasting evolutionary outcomes from a second long-term co-evolutionary experiment. Using a droplet flow reactor system with increased dilution frequency over 5000 h (1,600 generations), we observed reduced diversity and frequent extinctions in later experimental stages. Co-replication assays of RNA clones revealed that the primary cause of this diversity loss was the shortened reaction time resulting from frequent dilution. Further analysis of RNA clones that emerged during evolution suggested that the frequent extinctions resulted from the appearance of highly competitive parasite species and the dominance of host species that exhibited reduced replication ability. These findings demonstrate that co-evolution between host and parasitic replicators can result in diversity loss and frequent extinctions depending on dilution conditions, highlighting the critical role of environmental parameters, such as dilution ratio and frequency, in enabling primitive replicators to evolve sustainably toward the emergence of life.

evolutionary biology↗

bioRxiv2022

Emergence of linkage between cooperative RNA replicators encoding replication and metabolic enzymes thorough experimental evolution

The integration of individually replicating genes into a primitive chromosome is a key evolutionary transition in the development of life, allowing the simultaneous inheritance of genes. However, how this transition occurred is unclear because of the extended size of primitive chromosomes, which replicate slower than unlinked genes. Theoretical studies have suggested that a primitive chromosome can evolve in the presence of cell-like compartments, as the physical linkage prevents the stochastic loss of essential genes upon division, but experimental support for this is lacking. Here, we demonstrate the evolution of a chromosome-like RNA from two cooperative RNA replicators encoding replication and metabolic enzymes. Through their long-term replication in cell-like compartments, linked RNAs emerged with the two cooperative RNAs connected end-to-end. The linked RNAs had different mutation patterns than the two unlinked RNAs, suggesting that they were maintained as partially distinct lineages in the population. Our results provide experimental evidence supporting the plausibility of the evolution of a primitive chromosome from unlinked gene fragments, an important step in the emergence of complex biological systems. Author SummaryThe integration of genes into a chromosome is a fundamental genetic organization in all extant life. The assembly of unlinked genes during prebiotic evolution was likely a major evolutionary transition toward the development of a complex cell. Decades of theoretical studies have suggested a plausible evolutionary pathway to a primitive chromosome from replicating RNA molecules that harbor cooperative genes within a protocell structure. However, demonstrating the evolution of a primitive chromosome in an experimental setup is challenging. We previously developed a cooperative RNA replication system in which two types of RNAs co-replicate using their self-encoded replication and metabolic enzymes. Using this system, in the present study, we demonstrate the evolution of a linkage between the two cooperative RNA replicators in compartments. An evolved "linked" RNA harbored the entire region of both genes, accumulated distinct mutations, and retained the ability to replicate using the two proteins translated from itself. These experimental findings support a prebiotic evolutionary scenario, in which unlinked genes assembled into a single genomic structure.

evolutionary biology↗

bioRxiv2022

Plausible pathway for a host-parasite molecular replication network to increase its complexity through Darwinian evolution

How the complexity of primitive self-replication molecules develops through Darwinian evolution remains a mystery with regards to the origin of life. Theoretical studies have proposed that coevolution with parasitic replicators increases network complexity by inducing inter-dependent replication. However, the feasibility of such complexification with biologically relevant molecules is still unknown owing to the lack of an experimental model. Here, we investigated the plausible complexification pathway of host-parasite replicators using both an experimental host-parasite RNA replication system and a theoretical model based on the experimental system. We first analyzed the parameter space that allows for sustainable replication in various replication networks ranging from a single molecule to three-member networks using computer simulation. The analysis shows that the most plausible complexification pathway from a single host replicator is the addition of a parasitic replicator, followed by the addition of a new host replicator that is resistant to the parasite. We also provide evidence that the pathway actually occurred in our previous evolutionary experiment. These results provide both a theoretical basis and experimental evidence that a single replicator spontaneously develops into multi-replicator networks through coevolution with parasitic replicators, which might be the first complexification step toward to the emergence of life.

evolutionary biology↗

bioRxiv2021

Evolutionary transition from a single RNA replicator to a multiple replicator network

In prebiotic evolution, self-replicating molecules are believed to have evolved into complex living systems by expanding their information and functions open-endedly. Theoretically, such evolutionary complexification could occur through successive appearance of novel replicators that interact with one another to form replication networks. Here we performed long-term evolution experiments using an RNA that replicates by a self-encoded RNA replicase. The RNA diversified into multiple coexisting host and parasite lineages, whose frequencies in the population initially fluctuated and gradually stabilized. The final population, comprising five RNA lineages, forms a replicator network with diverse interactions, including cooperation to help the replication of all other members. These results support the capability of molecular replicators to spontaneously develop complexity through Darwinian evolution, a critical step for the emergence of life.

evolutionary biology↗