Eörs Szathmáry

The origin of replicators and reproducers

Replicators are fundamental to the origin of life and evolvability. Their survival depends on the accuracy of replication and the efficiency of growth relative to spontaneous decay. Infrabiological systems are built of two coupled autocatalytic systems, in contrast to minimal living systems that must comprise at least a metabolic subsystem, a hereditary subsystem and a boundary, serving respective functions. Some scenarios prefer to unite all these functions into one primordial system, as illustrated in the lipid world scenario, which is considered as a didactic example in detail. Experimentally produced chemical replicators grow parabolically owing to product inhibition. A selection consequence is survival of everybody. The chromatographized replicator model predicts that such replicators spreading on surfaces can be selected for higher replication rate because double strands are washed away slower than single strands from the surface. Analysis of real ribozymes suggests that the error threshold of replication is less severe by about one order of magnitude than thought previously. Surface-bound dynamics is predicted to play a crucial role also for exponential replicators: unlinked genes belonging to the same genome do not displace each other by competition, and efficient and accurate replicases can spread. The most efficient form of such useful population structure is encapsulation by reproducing vesicles. The stochastic corrector model shows how such a bag of genes can survive, and what the role of chromosome formation and intragenic recombination could be. Prebiotic and early evolution cannot be understood without the models of dynamics.

Lack of evolvability in self-sustaining autocatalytic networks constraints metabolism-first scenarios for the origin of life

A basic property of life is its capacity to experience Darwinian evolution. The replicator concept is at the core of genetics-first theories of the origin of life, which suggest that self-replicating oligonucleotides or their similar ancestors may have been the first “living” systems and may have led to the evolution of an RNA world. But problems with the nonenzymatic synthesis of biopolymers and the origin of template replication have spurred the alternative metabolism-first scenario, where self-reproducing and evolving proto-metabolic networks are assumed to have predated self-replicating genes. Recent theoretical work shows that “compositional genomes” (i.e., the counts of different molecular species in an assembly) are able to propagate compositional information and can provide a setup on which natural selection acts. Accordingly, if we stick to the notion of replicator as an entity that passes on its structure largely intact in successive replications, those macromolecular aggregates could be dubbed “ensemble replicators” (composomes) and quite different from the more familiar genes and memes. In sharp contrast with template-dependent replication dynamics, we demonstrate here that replication of compositional information is so inaccurate that fitter compositional genomes cannot be maintained by selection and, therefore, the system lacks evolvability (i.e., it cannot substantially depart from the asymptotic steady-state solution already built-in in the dynamical equations). We conclude that this fundamental limitation of ensemble replicators cautions against metabolism-first theories of the origin of life, although ancient metabolic systems could have provided a stable habitat within which polymer replicators later evolved.

In silico simulations reveal that replicators with limited dispersal evolve towards higher efficiency and fidelity

The emergence of functional replicases, acting quickly and with high accuracy, was crucial to the origin of life. Although where the first RNA molecules came from is still unknown, it is nevertheless assumed that catalytic RNA enzymes (ribozymes) with replicase function emerged at some early stage of evolution. The fidelity of copying is especially important because the mutation load limits the length of replicating templates that can be maintained by natural selection. An increase in template length is disadvantageous for a fixed digit copying fidelity, however, longer molecules are expected to be better replicases. An iteration for longer molecules with better replicase function has been suggested and analysed mathematically. Here we show that more efficient replicases can spread, provided they are adsorbed to a prebiotic mineral surface. A cellular automaton simulation reveals that copying fidelity, replicase speed and template efficiency all increase with evolution, despite the presence of molecular parasites, essentially because of reciprocal atruism (‘within-species mutualism’) on the surface, thus making a gradual improvement of replicase function more plausible.

Sub-exponential growth and coexistence of non-enzymatically replicating templates*

The experimentally reported kinetic behaviour (sub-exponential but supra-linear growth) of non-enzymatic template replication is incorporated into a simple model of template competition. Sub-exponential growth is shown to lead to coexistence invariably. Thus coexistence of different non-enzymatically replicating sequences is predicted. This type of coexistence could have been important in maintaining a sufficient diversity of RNA modules used later to build functional molecules such as ribozymes. Experimental tests of this theoretical prediction are possible.

Toward major evolutionary transitions theory 2.0

The impressive body of work on the major evolutionary transitions in the last 20 y calls for a reconstruction of the theory although a 2D account (evolution of informational systems and transitions in individuality) remains. Significant advances include the concept of fraternal and egalitarian transitions (lower-level units like and unlike, respectively). Multilevel selection, first without, then with, the collectives in focus is an important explanatory mechanism. Transitions are decomposed into phases of origin, maintenance, and transformation (i.e., further evolution) of the higher level units, which helps reduce the number of transitions in the revised list by two so that it is less top-heavy. After the transition, units show strong cooperation and very limited realized conflict. The origins of cells, the emergence of the genetic code and translation, the evolution of the eukaryotic cell, multicellularity, and the origin of human groups with language are reconsidered in some detail in the light of new data and considerations. Arguments are given why sex is not in the revised list as a separate transition. Some of the transitions can be recursive (e.g., plastids, multicellularity) or limited (transitions that share the usual features of major transitions without a massive phylogenetic impact, such as the micro- and macronuclei in ciliates). During transitions, new units of reproduction emerge, and establishment of such units requires high fidelity of reproduction (as opposed to mere replication).

Real ribozymes suggest a relaxed error threshold

The error threshold for replication, the critical copying fidelity below which the fittest genotype deterministically disappears, limits the length of the genome that can be maintained by selection. Primordial replication must have been error-prone, and so early replicators are thought to have been necessarily short. The error threshold also depends on the fitness landscape. In an RNA world, many neutral and compensatory mutations can raise the threshold, below which the functional phenotype, rather than a particular sequence, is still present. Here we show, on the basis of comparative analysis of two extensively mutagenized ribozymes, that with a copying fidelity of 0.999 per digit per replication the phenotypic error threshold rises well above 7,000 nucleotides, which permits the selective maintenance of a functionally rich riboorganism with a genome of more than 100 different genes, the size of a tRNA. This requires an order of magnitude of improvement in the accuracy of in vitro–generated polymerase ribozymes. Incidentally, this genome size coincides with that estimated for a minimal cell achieved by top-down analysis, omitting the genes dealing with translation.

Comparable system-level organization of Archaea and Eukaryotes

A central and long-standing issue in evolutionary theory is the origin of the biological variation upon which natural selection acts. Some hypotheses suggest that evolutionary change represents an adaptation to the surrounding environment within the constraints of an organisms innate characteristics. Elucidation of the origin and evolutionary relationship of species has been complemented by nucleotide sequence and gene content analyses, with profound implications for recognizing lifes major domains. Understanding of evolutionary relationships may be further expanded by comparing systemic higher-level organization among species. Here we employ multivariate analyses to evaluate the biochemical reaction pathways characterizing 43 species. Comparison of the information transfer pathways of Archaea and Eukaryotes indicates a close relationship between these domains. In addition, whereas eukaryotic metabolic enzymes are primarily of bacterial origin, the pathway-level organization of archaeal and eukaryotic metabolic networks is more closely related. Our analyses therefore suggest that during the symbiotic evolution of eukaryotes, incorporation of bacterial metabolic enzymes into the proto-archaeal proteome was constrained by the hosts pre-existing metabolic architecture.

Multicellularity: evolution and the egg.

Most multicellular organisms pass through a single-cell stage from which they then develop. This feature may render them more evolvable.

The evolution of information storage and heredity.

Many important transitions in evolution are associated with novel ways of storing and transmitting information. The storage of information in DNA sequence, and its transmission through DNA replication, is a fundamental hereditary system in all extant organisms, but it is not the only way of storing and transmitting information, and has itself replaced, and evolved from, other systems. A system that transmits information can have limited heredity or indefinite heredity. With limited heredity, the number of different possible types is commensurate with, or below, that of the individuals. With indefinite heredity, the number of possible types greatly exceeds the number of individuals in any realistic system. Recent findings suggest that the emergence and subsequent evolution of very different hereditary systems, from autocatalytic chemical cycles to natural language, accompanied the major evolutionary transitions in the history of life.

Life: In search of the simplest cell

Top-down, bottom-up; RNA-based, lipid-based; theory, experiment — there are many different ways of investigating what constitutes a ‘minimal cell’. Progress requires finding common themes between them.