- Modelling evolution on design-by-contract predicts an origin of Life through an abiotic double-stranded RNA world
Reverse engineering the origin of Life
The dsRNA first hypothesis proposes a sequence of functional events for the evolution of the genome that is derived from engineering principles that enforces functional continuity by keeping existing interfaces intact [14,15]. The dsRNA first hypothesis can be separated into distinct mechanistic and functional steps: a) the abiotic formation of dsRNA as a starting point for Life, b) the replication of this dsRNA in order to conserve and multiply the potential informational carrier, c) the formation of catalytic ssRNA from specific proto-gene regions of dsRNA, d) extension of functionality by protein translation based on a single-stranded RNA template (mRNA), and e) the transition from dsRNA to dsDNA. In this process, extra functionality is added in gradual steps while keeping existing functionality intact. The initial abiotic replication and transcription process can be exchanged for an enzymatic one, the evolution towards mRNA as a template for translation is only an addition to existing functions of ssRNA, while the transition from dsRNA to dsDNA does not require a basic change in functional interface. Thus, the dsRNA scenario maintains functional continuity in an evolving and expanding system, one of the fundamental requirements of evolution.
The engineering paradigm design-by-contract defined clear guidelines for evolution of developmental sequences that could be translated into a biochemical implementation. The presented scenario is also in line with other engineering considerations for a putative evolving molecular machine. The proposed mechanistic scenario provides a physical driving force for replication and transcription, the perpetual diurnal cycle, offering the possibility for cycles of extensions and mutations and a general trend towards an increase in complexity. Also, the scenario is self-contained because all processes later in evolution are derived from, and contained within the first (informational) dsRNA molecule. This makes evolution in its entirety independent, in contrast to genetic takeover scenario's. Thus, the dsRNA hypothesis provides an alternative theory for the origin-of-life that can be based on the predicted power of the framework and the resulting system characteristics, together with the gradual mechanistic scenario that maintains functional continuity.
Microenvironments for early life
Although the dsRNA first hypothesis assumes the presence of short ribonucleotide strands or equivalents, the production of ribonucleotides still represents a challenge for prebiotic chemistry. A functional equivalent for RNA, for instance preRNA (see ), may substitute for the early abiotic processes that are suggested in this manuscript. The first formation of oligomers could have relied on a specific environment, for instance the surface of a catalytic mineral such as montmorillonite on which surface activated monomers could react to form short oligomers [42,43]. Some form of compartmentalization, for instance in liposomes or porous rock [44-46] may have provided the environment for early life when short strands of complementary oligonucleotides (see [17,42]) form in populations of abiotic microenvironments, for instance the pores of porous rock. Such abiotic microenvironments could later be functionally replaced by a cell membrane due to the evolution of lipid-generating enzymes . This replacement of the abiotic environment provides more environmental independence while such a genome-driven membrane formation will also give the biological cell a self-contained character.
Thermal cycling as the initial driving force for abiotic replication and transcription
The proposed melting and rehybridization cycles underlying the dsRNA-first hypothesis can be driven in a prebiotic environment by a diurnal cycle that amplifies and replicates populations of dsRNA. The perpetual night/day temperature cycles can in this view considered to be the driving force for the emergence of Life, creating an early potential for diversity and selection with each replication cycle. The thermal cycling PCR can in principle also occur in a steady temperature gradient where convection will cycle the DNA in and out of the higher temperature spot [47,48], widening the environments for an origin of life based on thermal cycling. Melting and hybridization steps are in principle also possible by tidal cycling  in combination with drying and increasing salt concentration, since increasing ionic strength also favors melting. The advent of biotic (enzymatic) replication and transcription process that replace the abiotic transcription processes would enable diurnal cycle independent evolution.
Evolutionary drive towards formation of catalytic RNA
Similar to the tendency of ribonucleotides to hybridize and ligate to form dsRNA, a driving force towards ssRNA could cause the further transition to catalytic RNA in evolution. The abiotic transcription process would be specifically enhanced for proto-genes that generate a folded RNA. Since folded RNA's are less likely to rehybridize with its template in the abiotic transcription process, they avoid the product inhibition observed in other replicating systems . Ribozymes and catalytic RNA are characterized by their folding into a three-dimensional structure like hairpin loops, and in combination with random mutation, a selection can take place for folded RNA with catalytic abilities. Selection of protocells in which ssRNA is generated that can specifically aid in the replication process may lead to selection for autocatalytic populations of dsRNA and may be considered to be proto-genomes. The emergence of ribozymes may also aid in the generation of genetic diversity by catalyzing splicing and ligation of RNA strands (cf. the role of introns; ).
A design framework for evolution
Design-by-contract  forms a simple straightforward framework to design complex systems that need to be extensible and robust. Evolutionary steps can be modelled on this engineering paradigm by defining evolution as an expanding system of functionalities that are connected by well-defined and constant interfaces. The effect of designing interfaces across modules is a reduction of the interdependencies across modules or components and a reduction of the risk that changes within one module will create unanticipated changes in other modules. By identifying the functional modules and their conserved interfaces in evolution, it becomes possible to reconstruct the mechanistic scenarios underlying evolution. Here, an analysis of the interfaces for transcription and translation defined dsRNA as the logical first step towards an expanding genome. This approach led to a relative simple scenario for the origin of Life that makes a gradual scenario for genome evolution feasible. The same approach has recently also led to new scenario's for the origin of introns  and the origin of the eukaryotic cell  and shows the explanatory power of modelling evolution on design-by-contract and viewing Life as a self-evolving molecular machine.
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