Origins of Life: A plausible route to the first genetic alphabet

These GEITP pages include the topic of evolution, which of course includes the origins of life on this planet (which might have occurred as early as 4.2 to 4.0 billion years ago). The genetic polymers RNA and DNA are central to information storage in all biological systems and, as such, form the core of most hypotheses about the origin of life. The most prominent of these theories is the “RNA world” hypothesis, which postulates that RNA was once both the central information-carrier and the catalyst for biochemical reactions on Earth before the emergence of life. Studies in the past few years, however, have suggested that the first genetic systems might have been based on nucleic-acid molecules that contain both RNA and DNA nucleotides — which then gradually self-separated into today’s RNA and DNA.

Authors [see attached article & editorial] offer fascinating experimental support for an initial mixed RNA–DNA world. Primordial geochemical processes are thought to have led to formation of the building blocks of nucleic acids — nucleotides, and nucleosides (nucleotides that lack a phosphate group). Under suitable conditions, these building blocks polymerized and the resulting strands would eventually have to be replicated, without assistance from modern protein enzymes. How could this have happened? These authors previously had identified a network of reactions (promoted by ultraviolet light) that resulted in synthesis of two of the standard nucleosides found in RNA: uridine (U) and cytidine (C) — (known collectively as pyrimidines). These reactions started from hydrogen cyanide (HCN) and derivatives thereof, simple molecules, thought to have been readily available — not only on many planets, comets and meteors throughout the universe — including early Earth.

Further studies and development of this reaction network raised the intriguing possibility that protein and lipid precursors could have arisen simultaneously alongside nucleosides — thereby providing three of the main types of molecules needed to make cells. However, a complementary route for formation of the other two standard RNA nucleosides [adenosine (A) and guanosine (G), i.e. the purines), using the same HCN-based chemistry, has remained elusive.

In the present work [see attached], authors revisited compounds produced as intermediates in the previously established reaction network that synthesizes U and C; they identified a pathway in which a key intermediate of pyrimidine-nucleoside synthesis, ribo-aminooxazoline (RAO; see fantastic diagram of the chemical ppathways in editorial), can also be converted into two purine DNA nucleosides, deoxyadenosine (dA) and deoxyinosine (dI, which is not one of the standard nucleosides found in modern DNA). Intriguingly, these DNA nucleosides can form base pairs with U and C.

The four nucleosides — U, C, dA and dI — therefore constitute a complete “alphabet” that could have encoded genetic information in nucleic acids in a prebiotic RNA–DNA world. Importantly, the synthesis of dA and dI can occur in parallel with that of U and C, producing mixtures of the four products — in yields and ratios suitable for the construction of a genetic system. This mutual compatibility of the two synthetic pathways increases plausibility of the reaction network as a prebiotic system: if the two syntheses were incompatible, then geological scenarios would need to be contrived to explain how they could have been separated into different pools to enable the chemistry to occur, and then combined to enable the formation of hybrid RNA–DNA molecules. Notably, under certain reaction conditions, U and C can survive only in the presence of the thio-anhydro-purine compounds that act as direct precursors of dA and dI.

In summary, authors have demonstrated a high-yielding, completely stereo-, regio- and furanosyl-selective prebiotic synthesis of the purine deoxyribonucleosides: dA and dI. Their synthesis uses key intermediates found in the prebiotic synthesis of the canonical pyrimidine ribonucleosides (C and U). Authors show that, once generated, the pyrimidines persist throughout the synthesis of the purine deoxyribonucleosides — leading to a mixture of dA, dI, C and U. These results would support the notion that purine deoxyribonucleosides and pyrimidine ribonucleosides may have co-existed before the emergence of life on this planet. 😊

Nature 4 June 2020; 582: 60-66 + editorial pp 33-34?

COMMENT: The publication offered by Prof. Lancet is attached as the third item above (Life 2019, 9: 77; doi:10.3390/life9040077).


Dear Dan, Good to see yet-another Origins-Of-Life (OOL) paper among the many papers you recommend, and which are made understandable by your excellent summaries!

The present OOL story no doubt helps establish the DNA-RNA world as a plausible life’s origin path. But — in stark conceptual contrast lies the more general, chemically-unbiased scheme in which life, which certainly began with a highly complex chemical mixture, emerged via an early reproduction mechanism much more compatible with environmental compound diversity. This scenario is different from (and independent of) mutually-templating polynucleotides as first reproducers. This scenario becomes possible, based on the concept of a lipid world (see recent paper attached and references therein).

In this conceptual framework, “lipid” stands for ANY amphiphile [any organic compound (e.g. detergent, bile salt, or phospholipid, surfactant), comprising both a water-loving and lipid-loving portion] — including such that have as headgroups a nucleobase, amino acid, or sugar, as well as any of thousands upon thousands of (sometime “nameless”) prebiotically plausible small molecules. Reproduction happens when micelles made of such lipids grow and split, transmitting compositional information from one generation to another. This, of course, necessitates that lipid micelles will portray catalytic capacities, as evidenced by a broad literature we are now summarizing in an in-preparation review.

Such a path of life’s origin transpires in a way that does not necessarily depend on the orthodoxy of nucleotide-base pairing: i.e. any event of molecular complementarity will do! The utterly specific roles of RNA and DNA as sequence-based information carriers and protein-encoding entities are then proposed to be a much later evolutionary emergent phenomenon. Importantly, our scenario is free of the setting in which any full-fledged system of replication polynucleotides had to miraculously become protein-encoding. The “lipid-world compositional reproduction setup” then allows co-evolution of the polynucleotide encoders, and the encoded polypeptides — in very small, more plausible steps.

The paper you have reviewed for us is highly relevant — as a key monomer supply scenario. But the alternative lipid world scenario, if further validated, bears a recommendation to employ similar eye-opening chemical scrutiny for the emergence of alternative molecular alphabets, including a diversity of functionalized lipids, to afford the overall understanding of life’s origins.

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