The Persistent Contributions of RNA to Eukaryotic Gen(om)e Architecture and Cellular Function

Currently, the best scenario for earliest forms of life is based on RNA molecules as they have the proven ability to catalyze enzymatic reactions and harbor genetic information. Evolutionary principles valid today become apparent in such models already. Furthermore, many features of eukaryotic genome architecture might have their origins in an RNA or RNA/protein (RNP) world, including the onset of a further transition, when DNA replaced RNA as the genetic bookkeeper of the cell. Chromosome maintenance, splicing, and regulatory function via RNA may be deeply rooted in the RNA/RNP worlds. Mostly in eukaryotes, conversion from RNA to DNA is still ongoing, which greatly impacts the plasticity of extant genomes. Raw material for novel genes encoding protein or RNA, or parts of genes including regulatory elements that selection can act on, continues to enter the evolutionary lottery.

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Sturgeon''s Revelation: Ninety percent of science fiction is crud, but then, ninety percent of everything is crud.—Theodore Sturgeon

They think that intelligence is about noticing things that are relevant (detecting patterns); in a complex world, intelligence consists in ignoring things that are irrelevant (avoiding false patterns).—Nassim Nicholas Taleb (Taleb 2010)

Of all extant cellular macromolecules, RNA is the most ancient, persisting as much as 4 × 10⁹ years in our planet’s life-forms. The ability to combine genotype with phenotype such as catalytic activity (Noller and Chaires 1972; Kruger et al. 1982; Guerrier-Takada et al. 1983; Noller et al. 1992) leveled a major hurdle in understanding the origin of life. The salient discoveries eliminated the virtually impossible prerequisite for two to three different classes of macromolecules to converge as an evolving unit. At the same time, RNA provides a required continuity in the path of evolution (Yarus 2011) during various genetic takeovers or evolutionary transitions (Cairns-Smith 1982; Szathmáry and Smith 1995). In a remarkably insightful article dating back half a century, Alex Rich foresaw much of what now is becoming mainstream, for example, that RNA was ancestral to protein and DNA (Rich 1962). This landmark publication received little attention over the years; even early proponents of an RNA world did not refer to this article (Woese 1967; Crick 1968; Orgel 1968; Gilbert 1986), although at least one of the investigators must have had knowledge about the article, as it was cited in a different context concerning the stereochemical possibility of six distinct base pairs (Crick 1968). The origin of the DNA genome from RNA and that “DNA may be regarded as a derivative molecule which has evolved in the form that it only carries out part of the primitive nucleic acid function” is another correct prediction (Rich 1962). Furthermore, the investigator presaged mechanisms such as antisense RNA control of gene expression, short interfering RNAs (siRNAs), and perhaps microRNAs (miRNAs): “If both strands are active, then the DNA would produce two RNA strands which are complementary to each other. Only one of these might be active in protein synthesis, and the other strand might be a component of the control or regulatory signal” (Rich 1962).In this article, I shall present the rise and persistence of RNA from the dawn of an RNA world and discuss current evolutionary principles already apparent in an RNA world. In comparison to Archaea and Bacteria, the eukaryotic genome is a better vantage point, as archaeal and bacterial genomes are more derived and, thus, lost many of the RNA signatures that eukaryotes still show. It is likely that eukaryotic DNA genomes not only kept much more of their RNA/RNP world heritage than previously anticipated, but also continue to evolve novel RNAs in various functional roles.