I. the origin of species by means of natural selection

In vitro selection allows rare functional RNA or DNA molecules to be isolated from pools of over 10(15) different sequences. This approach has been used to identify RNA and DNA ligands for numerous small molecules, and recent three-dimensional structure solutions have revealed the basis for ligand recognition in several cases. By selecting high-affinity and -specificity nucleic acid ligands for proteins, promising new therapeutic and diagnostic reagents have been identified. Selection experiments have also been carried out to identify ribozymes that catalyze a variety of chemical transformations, including RNA cleavage, ligation, and synthesis, as well as alkylation and acyl-transfer reactions and N-glycosidic and peptide bond formation. The existence of such RNA enzymes supports the notion that ribozymes could have directed a primitive metabolism before the evolution of protein synthesis. New in vitro protein selection techniques should allow for a direct comparison of the frequency of ligand binding and catalytic structures in pools of random sequence polynucleotides versus polypeptides.

/pdf/in-vitro-selection-of-functional-nucleic-acids-2gyp6kaqym.pdf

In vitro selection of functional nucleic acids.

Cryptic variation is caused by the robustness of phenotypes to mutations Cryptic variation has no effect on phenotypes in a given genetic or environmental background, but it can have effects after mutations or environmental change Because evolutionary adaptation by natural selection requires phenotypic variation, phenotypically revealed cryptic genetic variation may facilitate evolutionary adaptation This is possible if the cryptic variation happens to be pre-adapted, or "exapted", to a new environment, and is thus advantageous once revealed However, this facilitating role for cryptic variation has not been proven, partly because most pertinent work focuses on complex phenotypes of whole organisms whose genetic basis is incompletely understood Here we show that populations of RNA enzymes with accumulated cryptic variation adapt more rapidly to a new substrate than a population without cryptic variation A detailed analysis of our evolving RNA populations in genotype space shows that cryptic variation allows a population to explore new genotypes that become adaptive only in a new environment Our observations show that cryptic variation contains new genotypes pre-adapted to a changed environment Our results highlight the positive role that robustness and epistasis can have in adaptive evolution

/pdf/cryptic-genetic-variation-promotes-rapid-evolutionary-5a9shs1xr8.pdf

Cryptic genetic variation promotes rapid evolutionary adaptation in an RNA enzyme

To what extent are evolutionary outcomes determined by a population's recent environment, and to what extent do they depend on historical contingency and random chance? Here we apply a unique experimental system to investigate evolutionary reproducibility and path dependence at the protein level. We combined phage-assisted continuous evolution with high-throughput sequencing to analyze evolving protein populations as they adapted to divergent and then convergent selection pressures over hundreds of generations. Independent populations of T7 RNA polymerase genes were subjected to one of two selection histories (“pathways”) demanding recognition of distinct intermediate promoters followed by a common final promoter. We observed distinct classes of solutions with unequal phenotypic activity and evolutionary potential evolve from the two pathways, as well as from replicate populations exposed to identical selection conditions. Mutational analysis revealed specific epistatic interactions that explained the observed path dependence and irreproducibility. Our results reveal in molecular detail how protein adaptation to different environments, as well as stochasticity among populations evolved in the same environment, can both generate evolutionary outcomes that preclude subsequent convergence.

https://www.pnas.org/content/pnas/110/22/9007.full.pdf

Experimental interrogation of the path dependence and stochasticity of protein evolution using phage-assisted continuous evolution.

Evolutionary origins and directed evolution of RNA.

In the course of evolving variants of the Tetrahymena thermophila Group I ribozyme for improved DNA cleavage in vitro, we witnessed the unexpected emergence of a derived molecular species, capable of acting as a partner for the ribozyme, but no longer autocatalytic. This new RNA species exhibits a deletion in the catalytic core and participates in a productive intermolecular interaction with an active ribozyme, thus insuring its survival in the population. These novel RNA molecules have evolved a precise catalytic interaction with the Group I ribozyme and depend for their survival on the continued presence of active catalysts. This interaction hints at the complexity that may inevitably arise even in simple evolving systems.

Experimental evolution of complexity: in vitro emergence of intermolecular ribozyme interactions.

In order to explore the variety of possible responses available to a ribozyme population evolving a novel phenotype, five Tetrahymena thermophila group I intron ribozyme pools were evolved in parallel for cleavage of a DNA oligonucleotide. These ribozyme populations were propagated under identical conditions and characterized when they reached apparent phenotypic plateaus; the populations that reached the highest plateau showed a near 100-fold improvement in DNA cleavage activity. A detailed characterization of the evolved response in these populations reveals at least two distinct phenotypic trajectories emerging as a result of the imposed selection. Not only do these distinct solutions exhibit differential DNA cleavage activity, but they also exhibit a very different correlation with a related, but unselected, phenotype: RNA cleavage activity. In turn, each of these trajectories is underwritten by differing genotypic profiles. This study underscores the complex network of possible trajectories through sequence space available to an evolving population and uncovers the diversity of solutions that result when the process of experimental evolution is repeated multiple times in a simple, engineered system.

/pdf/replicability-and-recurrence-in-the-experimental-evolution-45vyy8rws5.pdf

Replicability and Recurrence in the Experimental Evolution of a Group I Ribozyme

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Experimental evolution of complexity: in vitro emergence of intermolecular ribozyme interactions.

Replicability and Recurrence in the Experimental Evolution of a Group I Ribozyme