Prebiotikus és mikrobiális kooperatív rendszerek evolúciójának térben explicit modellezése = Spatially explicit models for the evolution of prebiotic and microbial cooperation

A jelen OTKA-pályázati támogatás keretében elvégzett munkánkat 14 cikkben publikáltuk. Ezek közül 8 jelent meg rangos nemzetközi folyóiratokban, 3 az ""Ökológia"" címmel 2009-ben megjelent tankönyv fejezete, és 3 magyar nyelvű ismeretterjesztő cikk, amelyek közül kettő a Magyar Tudomány-ban, más tudományterületek szakértői számára, egy pedig a szélesebb közönség számára íródott. A kutatási program 3 alprogramra osztható, melyek közös foglalata részben koncepcionális, részben módszertani jellegű. Mindhárom al-téma közvetlenül az evolválódó entitások populációinak térbeli és időbeli dinamikájához kapcsolódik. Az említett entitások lehetnek prebiotikus replikátor-molekulák (az RNS-világ fajainak képviselői), ill. mikro- vagy makroorganizmusok. Kérdéseink ezek populációinak együttélési feltételeire, valamint a dinamikából következő (ko-)evolúciós viszonyaikra vonatkoznak, különböző tér- és időbeli léptékekben. Elméleti eredményeink némelyikét laboratóriumban teszteltük, ill. azok tesztelése folyamatban van. | The results of our research supported by this OTKA project have been summarized in 14 papers, of which 8 are published in high-ranking international journals, 3 are textbook chapters and 3 are reviews of our work, intended either for the professional or the general public, in Hungarian. The project is divided into 3 sub-projects, the common framework of which is partly conceptual and partly methodological. All of the three sub-topics are directly related to the spatio-temporal dynamics of evolving entities which may be populations of either prebiotic replicators or of micro- and macroorganisms. Our questions are directed towards the possible coexistence of such entities on different spatial and temporal scales, and the possible (co-)evolution of their populations thereof. Some of our theoretical results have been (and are being) tested int he lab

In silico virológia és immunológia: modellezés, szimuláció és adatelemzés = In silico virology and immunology: modelling, simulation and data analysis

A pályázat keretében a HIV-fertőzés folyamatait vizsgáltuk a molekulák szintjétől egészen a járványok szintjéig, a matematikai és szimulációs modellezés, illetve a komplex adatelemzés módszereinek segítségével. A molekulák szintjén modelleztük a vírusrészecskék érésének legfontosabb folyamatát, ami segíthet az érést gátló gyógyszerek hatásának megértésében és optimalizálásában. Molekuláris (szekvencia-) adatok elemzésével a vírus életciklusáról, az immunrendszer és a HIV kölcsönhatásáról, valamint az újabb vírustörzzsel való felülfertőződés gyakoriságáról és következményeiről tudtunk meg fontos részleteket. A felülfertőződés hatását a szervezetben zajló folyamatokat leíró matematikai modellekkel is vizsgáltuk, és hasonló módszerekkel elemeztük a HIV virulenciájára (betegségokozó képességére) ható szelekciós erőket. Populáció szintű klinikai adatok analízisével a virulencia lassuló emelkedését mutattuk ki az amerikai és európai járványokban. Végül járványtani szimulációkkal vizsgáltuk, milyen tényezők segíthették a HIV-járvány elindulását Közép-Afrikában a 20. század első felében. | We studied the processes of HIV infection from the level of molecules up to the level of epidemics, using mathematical and simulation modelling, and complex data analysis. At the level of molecules we modelled the crucial processes of the maturation of HIV virions, which might help us better understand the action of drugs targeted at virus maturation and to optimize therapy. By analyzing molecular (sequence) data we gleaned important new insights into the life cycle of the virus, the interactions between HIV and the immune system, and into the frequency and consequences of superinfection by a second virus strain. We further studied the effect of superinfection with mathematical models of virus dynamics, and utilized this technique also to investigate some of the selection forces acting on HIV virulence. In analyses of population scale clinical data we found an increasing (albeit decelerating) trend in HIV virulence in the epidemics of North America and Europe. Finally, we developed epidemics simulations to elucidate the factors that might have enabled the emergence of HIV epidemics in Central Africa in the first half of the 20th century

Prebiotic replicase evolution in a surface-bound metabolic system: parasites as a source of adaptive evolution

<p>Abstract</p> <p>Background</p> <p>The remarkable potential of recent forms of life for reliably passing on genetic information through many generations now depends on the coordinated action of thousands of specialized biochemical "machines" (enzymes) that were obviously absent in prebiotic times. Thus the question how a complicated system like the living cell could have assembled on Earth seems puzzling. In seeking for a scientific explanation one has to search for step-by-step evolutionary changes from prebiotic chemistry to the emergence of the first proto-cell.</p> <p>Results</p> <p>We try to sketch a plausible scenario for the first steps of prebiotic evolution by exploring the ecological feasibility of a mineral surface-bound replicator system that facilitates a primitive metabolism. Metabolism is a hypothetical network of simple chemical reactions producing monomers for the template-copying of RNA-like replicators, which in turn catalyse metabolic reactions. Using stochastic cellular automata (SCA) simulations we show that the surface-bound metabolic replicator system is viable despite internal competition among the genes and that it also maintains a set of mild "parasitic" sequences which occasionally evolve functions such as that of a replicase.</p> <p>Conclusion</p> <p>Replicase activity is shown to increase even at the expense of slowing down the replication of the evolving ribozyme itself, due to indirect mutualistic benefits in a diffuse form of group selection among neighbouring replicators. We suggest possible paths for further evolutionary changes in the metabolic replicator system leading to increased metabolic efficiency, improved replicase functionality, and membrane production.</p

Metabolically Coupled Replicator Systems: Overview of an RNA-world model concept of prebiotic evolution on mineral surfaces

Metabolically Coupled Replicator Systems (MCRS) are a family of models implementing a simple, physico-chemically and ecologically feasible scenario for the first steps of chemical evolution towards life. Evolution in an abiotically produced RNA-population sets in as soon as any one of the RNA molecules become autocatalytic by engaging in template directed self-replication from activated monomers, and starts increasing exponentially. Competition for the finite external supply of monomers ignites selection favouring RNA molecules with catalytic activity helping self-replication by any possible means. One way of providing such autocatalytic help is to become a replicase ribozyme. An additional way is through increasing monomer supply by contributing to monomer synthesis from external resources, i.e., by evolving metabolic enzyme activity. Retroevolution may build up an increasingly autotrophic, cooperating community of metabolic ribozymes running an increasingly complicated and ever more efficient metabolism. Maintaining such a cooperating community of metabolic replicators raises two serious ecological problems: one is keeping the system coexistent in spite of the different replicabilities of the cooperating replicators; the other is constraining parasitism, i.e., keeping "cheaters" in check. Surface-bound MCRS provide an automatic solution to both problems: coexistence and parasite resistance are the consequences of assuming the local nature of metabolic interactions. In this review we present an overview of results published in previous articles, showing that these effects are, indeed, robust in different MCRS implementations, by considering different environmental setups and realistic chemical details in a few different models. We argue that the MCRS model framework naturally offers a suitable starting point for the future modelling of membrane evolution and extending the theory to cover the emergence of the first protocell in a self-consistent manner. The coevolution of metabolic, genetic and membrane functions is hypothesized to follow the progressive sequestration scenario, the conceptual blueprint for the earliest steps of protocell evolution. (C) 2015 Elsevier Ltd. All rights reserved

The dynamics of the RNA world : Insights and challenges

The problem of the origin of life is not only one of structure but also that of dynamics. Ever since the seminal result of Manfred Eigen in 1971 showing that early template replication suffers from an error threshold, research has tackled the issue of how early genomes could have been dynamically stable without highly evolved mechanisms such as accurate replication and chromosomes. We review the theory of the origin, maintenance and enhancement of the RNA world as an evolving population of dynamical systems. Investigation of sequence space has revealed how structures are allocated in sequence space and how this affects the nature of the error threshold that sets the selectively maintainable genome length. New applications of old dynamical theory are still possible: the application of Gause’s principle of competitive exclusion, based on resource utilisation, to RNA replication predicts that at most four pairs (plus and minus strands) can stably be maintained on four nucleotides. Other mechanisms of early template coexistence should be regarded as additional means to raise the number of coexisting species above the number set by the competitive exclusion principle. One such example is the hypercycle in which templates were postulated to help replication of the next member in a cycle superimposed on individual replication cycles. Although the hypercycle is ecologically unstable it is evolutionarily unstable because it cannot efficiently compete against emerging parasites. Population structure can modify this conclusion but not without further qualification. The simplest form of population structure is limited diffusion on a surface. This simple mechanism can ensure the coexistence of competing ribozymes contributing to surface metabolism as well as the spread of efficient replicases despite the parasite problem. Hypercycles can only be saved by active compartmentalization when replicators are enclosed in reproducing protocells. Once there are protocells there is no need for internal hypercyclic organization, however. Finally we review two crucial adaptations that enhanced the RNA world: chromosomes and enzymatic metabolism. Interestingly, it was shown that these two have been presumably coevolutionarily linked because protocells harbouring unlinked, competing ribozymes are better off if the ribozymes remain inefficient but generalists. The appearance of chromosomes alleviates intragenomic conflict and is enabling constraint for the emergence of specific and efficient enzymes

The dynamics of the RNA world : Insights and challenges

The problem of the origin of life is not only one of structure but also that of dynamics. Ever since the seminal result of Manfred Eigen in 1971 showing that early template replication suffers from an error threshold, research has tackled the issue of how early genomes could have been dynamically stable without highly evolved mechanisms such as accurate replication and chromosomes. We review the theory of the origin, maintenance and enhancement of the RNA world as an evolving population of dynamical systems. Investigation of sequence space has revealed how structures are allocated in sequence space and how this affects the nature of the error threshold that sets the selectively maintainable genome length. New applications of old dynamical theory are still possible: the application of Gause’s principle of competitive exclusion, based on resource utilisation, to RNA replication predicts that at most four pairs (plus and minus strands) can stably be maintained on four nucleotides. Other mechanisms of early template coexistence should be regarded as additional means to raise the number of coexisting species above the number set by the competitive exclusion principle. One such example is the hypercycle in which templates were postulated to help replication of the next member in a cycle superimposed on individual replication cycles. Although the hypercycle is ecologically unstable it is evolutionarily unstable because it cannot efficiently compete against emerging parasites. Population structure can modify this conclusion but not without further qualification. The simplest form of population structure is limited diffusion on a surface. This simple mechanism can ensure the coexistence of competing ribozymes contributing to surface metabolism as well as the spread of efficient replicases despite the parasite problem. Hypercycles can only be saved by active compartmentalization when replicators are enclosed in reproducing protocells. Once there are protocells there is no need for internal hypercyclic organization, however. Finally we review two crucial adaptations that enhanced the RNA world: chromosomes and enzymatic metabolism. Interestingly, it was shown that these two have been presumably coevolutionarily linked because protocells harbouring unlinked, competing ribozymes are better off if the ribozymes remain inefficient but generalists. The appearance of chromosomes alleviates intragenomic conflict and is enabling constraint for the emergence of specific and efficient enzymes

Ecology and Evolution in the RNA World Dynamics and Stability of Prebiotic Replicator Systems

As of today, the most credible scientific paradigm pertaining to the origin of life on Earth is undoubtedly the RNA World scenario. It is built on the assumption that catalytically active replicators (most probably RNA-like macromolecules) may have been responsible for booting up life almost four billion years ago. The many different incarnations of nucleotide sequence (string) replicator models proposed recently are all attempts to explain on this basis how the genetic information transfer and the functional diversity of prebiotic replicator systems may have emerged, persisted and evolved into the first living cell. We have postulated three necessary conditions for an RNA World model system to be a dynamically feasible representation of prebiotic chemical evolution: (1) it must maintain and transfer a sufficient diversity of information reliably and indefinitely, (2) it must be ecologically stable and (3) it must be evolutionarily stable. In this review, we discuss the best-known prebiotic scenarios and the corresponding models of string-replicator dynamics and assess them against these criteria. We suggest that the most popular of prebiotic replicator systems, the hypercycle, is probably the worst performer in almost all of these respects, whereas a few other model concepts (parabolic replicator, open chaotic flows, stochastic corrector, metabolically coupled replicator system) are promising candidates for development into coherent models that may become experimentally accessible in the future

The Evolution of Enzyme Specificity in the Metabolic Replicator Model of Prebiotic Evolution

The chemical machinery of life must have been catalytic from the outset. Models of the chemical origins have attempted to explain the ecological mechanisms maintaining a minimum necessary diversity of prebiotic replicator enzymes, but little attention has been paid so far to the evolutionary initiation of that diversity. We propose a possible first step in this direction: based on our previous model of a surface-bound metabolic replicator system we try to explain how the adaptive specialization of enzymatic replicator populations might have led to more diverse and more efficient communities of cooperating replicators with two different enzyme activities. The key assumptions of the model are that mutations in the replicator population can lead towards a) both of the two different enzyme specificities in separate replicators: efficient “specialists” or b) a “generalist” replicator type with both enzyme specificities working at less efficiency, or c) a fast-replicating, non-enzymatic “parasite”. We show that under realistic trade-off constraints on the phenotypic effects of these mutations the evolved replicator community will be usually composed of both types of specialists and of a limited abundance of parasites, provided that the replicators can slowly migrate on the mineral surface. It is only at very weak trade-offs that generalists take over in a phase-transition-like manner. The parasites do not seriously harm the system but can freely mutate, therefore they can be considered as pre-adaptations to later, useful functions that the metabolic system can adopt to increase its own fitness