The current literature uses the term progenote in two different ways: It either signifies an organizational level that preceded cells with prokaryotic organization, or it is used to denote the last common ancestor of all extant life. In some scenarios describing early cellular evolution the last common ancestor was assumed to have been at a pre-prokaryotic level of organization; however, subsequent analyses of the molecular evolution of different cellular components suggest that the last common ancestor was a prokaryote. With this realization, the term progenote more properly should be used to denote a hypothetical pre-prokaryotic stage in cellular evolution, distinct from the last common ancestor.

          In 1977 Woese and Fox (1) defined the progenote as a hypothetical stage in the evolution of cells that preceded organisms with typical prokaryotic cellular organization: "Eucaryotes did arise from procaryotes, but only in the sense that the procaryotic is an organizational, not a phylogenetic distinction. In analogous fashion procaryotes arose from simpler entities. The latter are properly called progenotes, because they are still in the process of evolving the relationship between genotype and phenotype." The intention of Woese and Fox was to define an organizational level simpler than and preceding the prokaryotic level. At the progenotic level, genes and encoded proteins were smaller and the accuracy of transcription and translation was lower than at the prokaryotic level. As a result sequence evolution occurred more rapidly.

          At the prokaryotic level organisms contain a genome which encodes a multitude of biochemical and structural functions. Among the genome encoded functions present at the prokaryotic level are genome replication, translation of genomic information into functioning molecules, and formation of a semi-permeable barrier between the organism and its environment. Prokaryotic organization is so complex that the likelihood for the spontaneous assembly of a prokaryote from activated nucleotide and amino acid precursors present in a primordial soup is close to zero. A solution to this problem is to assume intermediate steps, which successively evolve into more complex structures. A usually assumed intermediate step in the origin of life are self-replicting RNA-like molecules. However, because of the limited accuracy of these early replicators, the size and information contained in these self-replicating molecules is limited (2).

          The evolution of a self propagating network of biochemical reactions that maintains a boundary with the environment, i.e., an autopoetic network (3), from simple self-replicating molecules is a major puzzle in the evolution of life. Most scenarios describing the evolution of cellular life include progenote-like organisms that are intermediate between the RNA-world and the first prokaryotes (e.g., 4; see Figure 1B). However, the progenote concept, postulating an organism without strict coupling between geno- and phenotype, partially negates the major conceptual breakthrough associated with the RNA-world, namely that Darwinian selection already acted on simple self-replicating RNA molecules. Regarding the evolution of progenotes, several questions remain open: How does natural selection act on an organism without strict coupling between geno- and phenotype? Can progenotes evolve by natural selection without a phenotype encoded by their genes? Is it feasible that selection took place only (or mainly) at the level of individual molecules, and not at the organismal level? Are alternative scenarios reasonable that assume a tight coupling between geno- and phenotype at the level of self-replicating molecules, and that maintain this coupling throughout the transition stages from the RNA world to the prokaryotic level (e.g., 2)?

          At the same time that the term progenote was introduced to describe a pre-prokaryotic stage of cellular organization, an alternative meaning of the term progenote originated. Woese and Fox (1) argued that the last common ancestor of bacteria and the eukaryotic nucleocytoplasmic component was a progenote. Later, this argument was extended to also include a third line of descent, the archaea or archaebacteria (5-7). Woese and collaborators suggested that the three domains or Urkingdoms might have evolved independently from the progenote, that the optimization of the transcription and translation machinery occurred in parallel in the three lines of descent, and that the last common ancestor might be equally related to each of the three domains (5-8, compare Fig. 1A). Unfortunately, the initial definitions were ambiguous, and potentially contradictory. Describing the evolution of bacteria and the eukaryotic nucleocytoplasmic component Woese and Fox (1) summarize "The two lines of descent, nevertheless shared a common ancestor, that was far simpler than the procaryote. This primitive entity is called a progenote, to denote the possibility that it had not yet completed evolving the link between geno and phenotype." Taken literally, this paragraph labels the ancestor of bacteria and eukaryotic nucleocytoplasm as progenote, and justifies the name choice by stating that the last common ancestor might have been at a pre-prokaryotic level of organization. As a result the term progenote is often used in the sense of progenitor to denote the last common ancestor of archaea, bacteria and eukaryotes; and not in the intended sense as a contrast to genote or eugenote, i.e., organisms with a "precise, accurate link between genotype and phenotype" (7).