The RNA World hypothesis

OLD Audio recording

Video recording (.mov format, 0.5Gbytes)
Video recording (480p .mp4 format, 0.1Gbytes)
Video recording (1080p .mp4 format, 0.4Gbytes


Life is based primarily on 3 major macromolecules: DNA, RNA and protein. It seems unlikely that these three emerged simultaneously, and so the question is, which was first? What might life have been like at such an early stage?

There are several reasons to think that RNA was most likely the first of these three macromolecules:

  1. DNA functions only through RNA intermediates (via transcription)
  2. the protein synthesis machinery is entirely RNA-based (mRNA, rRNA, tRNA)
  3. RNA can serve as genomes (information storage) in place of DNA (e.g. RNA viruses)
  4. RNA can catalyse chemical reactions in place of proteins (e.g. catalytic RNAs)

So RNA probably predates both DNA and protein, and therefore there probably was some form of an "RNA world" before the evolutionary invention of either DNA or protein. The alternative is that the three macromolecules, or perhaps RNA and protein, co-evolved . . . somehow.

The least obvious of the reasons cited above is the ability of RNA to catalyze chemical reactions. It turns out that not all enzymes are made of protein; some are made of RNA. The two known naturally-occuring catalytic RNAs are the lsu-rRNA (which catalyzes the peptidyl transferase activity of translation) and RNase P (which cleaved the 5ยด-leader from pre-tRNAs). There are also a number of naturally-occuring chemically-active RNAs that are not quite "catalytic" (and therefore not really enzymatic) because they are self-reactive: self-splicing RNAs (group I and II introns RNAs, nucelar splicosomal RNAs) and self-cleaving RNAs (delta virus RNAs, hammerhead and hairpin RNAs, Varkud mitochondrial RNA), &c. Most of these self-reactive RNAs can be converted to true catalysts by separating the catalytic and the substrate regions of the RNAs in enginered forms. In addition, a wide range of reactive and catalytic RNAs have been generated by in vitro selection.

RNAs can also perform other roles usually played by proteins. They can serve mechanical functions, e.g. the ribosomal RNAs that are the works of the translational apparatus, which really is a kind of natural nano-machine. RNAs can also perform structural roles and make biochemical decisions and transduce these decisions to other molecules, e.g. riboswitches, attenuators, terminators and anti-terminators, antisense RNAs, replication origin RNAs, &c, &c.

What could the RNA world have been like?

Two extreme scenarios are the "simple RNA world" and the "complex RNA world" scenarios.Reality (if there was an RNA World at all) could lie anywhere between these two extremes.

Simple RNA world scenario

In the simplest 'one molecule' RNA world scenario, a single self-replicating RNA might have contained both it's genetic information (genome) and the ability to replicate itself (function). Perhaps more likely, based on what we see today in RNA viruses, viroids, and virusoids, might be a 'two-RNA' world in which an RNA genome encoding an RNA replicase. Remember that most RNA viruses replicate through alternating (+) and (-) strand intermediates:

null or null


In this scenario, an RNA-based protein synthesis machinery might have emerged right away, presumably to make proteins that would be better than RNA at catalyzing other chemical reactions. A protein catalyst could then emerge to replace the simple RNA replicase (we would call this an RNA polymerase). In this scenario, only the genome, replicase, and translational apparatus were ever RNA:


The replacement of the RNA genome with more chemically stable DNA yeilds the modern system:



Complex RNA World scenario

In this scenario, an originally simple RNA world developed into an entire RNA-based metabolism, with all (or nearly all) of the current metabolic pathways and functions catalyzed by RNA enzymes rather than protein enzymes. These RNAs were subsequently replaced one-at-a-time by more efficient protein enzymes.


Proponents of this view consider nucleotide cofactors (e.g. ATP, GTP, NAD, FMN, etc) to be the vestiges of the original RNA enzymes. In this view, the RNA organisms would be cellular organisms, unlike the simple RNA world scenario in which this is not specified.

Problems with the RNA World hypothesis - reality check

Although almost universally accepted, there are some pretty significant shortcomings of the RNA world hypothesis that will need explaining, such as:

  1. In a simple RNA world, or early in a complex RNA world, where do the activated nucelotides (NTPs) come from for RNA polymerization? The generation of activated monomers is at least a difficult a task as their directed polymerization.
  2. RNA is far too complex isomerically. There are hundreds of pentose isomers, how do you specifically make D-ribose? The problem is that each nonfunctional isomer is a potential inhibitor of any process that the functional isomer is likely to engage in. The same issue also applies to the bases, and how you asemle them into polymers. The number of possible chemical isomers of even a short RNA chain are astronomical.
  3. RNA is very unstable, and is especially sensitive to metal ions, high temperature, and either high or low pH. How do you protect an RNA from damage, or even plain hydrolysis?

The avoid these problems, some have suggested that early precursors of RNA may have contained only purines (no pyrimidines - purines are easier to make abiotically)), and/or a non-ribose backbone (e.g. glycerol or peptide).

But where's the evidence? All of these ideas are pretty nebulous and, at least for now, untestable. So the RNA world view remains vague and disputed, but it is for now the best working hypothesis we have.