RNA world

{{Evolution}}
The '''RNA world''' [[hypothesis]] states that, before our [[DNA]]/[[RNA]]/[[protein]] world, there was once an RNA world, where RNA was both informational macromolecule (like DNA) and [[enzyme]] (like proteins). This hypothesis successfully solves several puzzles, though it has a few of its own.

==Reasons to believe there was a pre-DNA world==
The biggest puzzle is the origin of the DNA/RNA/protein system of all present-day cellular life. DNA is copied onto itself and onto RNA, and in turn, RNA is copied onto proteins. Which, in turn, catalyze all these reactions and do just about everything else. 

Related to this is the puzzle of why there are two kinds of nucleic acids instead of one: DNA and RNA. Adding to that puzzle, RNA is less chemically stable than DNA, which makes it seem superfluous. And since an early organism would have relatively poorly-developed maintenance and repair mechanisms, it might seem that such an organism could not afford to use RNA.

But despite DNA's greater stability, there is an abundance of evidence that it was RNA that had come before DNA, and not DNA before RNA.

'''Biosynthesis''' DNA is made from RNA. The deoxynucleotides are made from nucleotides with ribonucleotide reductases (RNR's), producing uracil-DNA or u-DNA. The uracil is then converted to thymine by adding a methyl group, making thymine-DNA or t-DNA, the kind that is actually used.

'''DNA replication''' RNA is involved in this process when one might expect it to be unnecessary. DNA polymerase needs to start from a RNA primer bound to the source strand.

'''Protein synthesis''' RNA -> protein translation involves some additional RNA's, the ribosomal and transfer RNA's. Amino acids are attached to transfer RNA's, which have an "anticodon" end that pairs with the messenger RNA. This pairing and the attachment to the forming protein chain are mediated by ribosomes, which contain both proteins and RNA's. And some experiments suggest that the ribosomes' RNA is their most essential part &mdash; the proteins are assistants.

'''Non-informational "stray" RNA''' RNA is present in a variety of non-informational contexts, while DNA is never present in such contexts; DNA is exclusively a master-copy molecule.

Bits of RNA are found in these enzyme cofactors:
:ATP (adenosine triphosphate, the nucleotide with extra phosphates)
:NAD (nicotinamide adenine dinucleotide) and NADP (NAD phosphate)
:FAD (flavin adenine dinucleotide) and FMN (flavin mononucleotide)
:Coenzyme A (contains pantothenate and adenosine)
:Cyclic AMP (adenosine monophosphate)
The first four of these are important in biosynthesis and electron-transfer metabolism; cyclic AMP is involved in intracellular signaling.

'''RNA enzymes''' Ribozymes are enzymes composed of RNA instead of protein. There are no corresponding DNA enzymes (deoxyribozymes) known in the wild, though a variety of such enzymes have been made in the lab.

'''Riboswitches''' These are bits of RNA that bind with metabolites and provide negative feedback in the form of interfering with the synthesis of enzymes for producing those metabolites, thus being involved in gene regulation. And here also, there is no known DNA counterpart.

We conclude that DNA emerged after RNA, as a modification of RNA.

==Reasons to believe RNA was the first molecule of life==
The previous section's discussion suggests that DNA/RNA/protein organisms are descended from RNA/protein ones; this reduces the complexity somewhat, but this leaves a fair amount of remaining complexity.

An important hint for solving this puzzle was discovered by Thomas Cech. In 1978, he started looking for a good example of an "intron" to study; introns are bits of genetic material snipped from messenger RNA before it can be used for anything. He decided to look at some ribosomal RNA of the ciliate protist ''Tetrahymena thermophila'', simply because it was easy to get large quantities of it from that source. He quickly discovered an intron in it, and he set to work studying how it gets spliced out. He made the extremely startling discovery that no enzyme was involved in splicing out that intron &mdash; that intron splices itself out! This was almost too bizarre to believe, and he became confident enough to announce it only in 1982. But he eventually won a [[Nobel Prize]] for this discovery. Since then, other self-splicing introns have been discovered, and ribozymes with additional functions are now known.

So could RNA have once done all the work now done by DNA and proteins? This hypothesis was proposed by [[Francis Crick]] in 1968, but the hypothesis only gained impetus after Cech's great discovery; the term "RNA world" was composed by Walter Gilbert in 1986. Using the honeybee analogy, the RNA world was a solitary-bee phase.

The RNA world would have had not only RNA-catalyzed RNA replication, but also various forms of metabolism, like electron-transfer metabolism, as indicated by the capabilities of cofactors like NAD. It could have had some biosynthesis capabilities, including synthesis of modified nucleotides in various contexts; nicotinamide, flavins, and other cofactor parts look much like modified RNA bases.

'''Leaving the RNA world.''' But how did the RNA world become the present DNA/RNA/protein world? What "bumblebees" were there? Did DNA originate first? Or did proteins? Or did they emerge together?

The origin of DNA is the simpler one; all that was necessary was to evolve RNR's and uracil-to-thymine. Enzymes could then be specialized for handling it &mdash; and for treating it as a precious heirloom, never to be used for anything but being a master copy. The necessity of RNA for initiating DNA replication suggests that the first DNA genome may have been heteroduplex &mdash; a DNA strand with a complementary RNA strand. DNA replication may have been incompletely elaborated in the last common ancestor of all present-day life; there are big differences between the replication systems of the domain [[Bacteria|Eubacteria]], on one side, and the domains Archaebacteria and [[Eukaryote|Eukarya]], on the other.

The origin of proteins is more difficult; it has been hard for scientists to find detailed scenarios for the origins of ribosomes and transfer RNA. However, there is a plausible path from ribozymes to proteins. The original ribozymes had amino-acid cofactors, and some of these were assembled to make the first protein cofactors. These protein cofactors were elaborated until they became most or all of the enzymes, with the RNA-containing parts being reduced to cofactors or otherwise vanishing altogether. Thus, like those RNA primers, the bits of RNA present in cofactors are [[vestigial features]].

Despite such difficulties, it has been possible to trace the [[evolution of the first proteins]]; this evolution strongly suggests that DNA emerged after proteins. To summarize, some metabolic and cell-membrane-associated proteins emerged before DNA-making and DNA-handling proteins.

'''The Origin of the RNA world.''' In spite of the successes of the RNA-world concept, there remains the serious question of the origin of this phase. A variety of molecules can be made by prebiotic-synthesis experiments, some of which have been observed in meteorites, interstellar space, and other such extraterrestrial locales. These include adenine and the simpler amino acids &mdash; but not ribose and other sugars. This has prompted some work on what could evolve into a RNA world, and one proposed candidate is Peptide Nucleic Acid (PNA), which consist of amino acids instead of ribose.

With a pre-RNA hypothesis, the question of how evolution into the RNA world occurred now presents itself. Why was ribose selected as the successor of the original backbone molecule? It may have been selected out of geometrical compatibility, in the same way that DNA is geometrically compatible with RNA. However, that leaves open the question of what made the ribose available - although a pre-RNA organism may have had some biosynthesis capabilities, including the ability to manufacture ribose.

==History of the concept and research==
The hypothesis that the first organisms were constructed from RNA was first suggested by Carl Woese in 1967, and a year later by Leslie Orgel and Francis Crick. The phrase ''RNA world'' was not coined until 1986, by Walter Gilbert.

In 2024, three scientists reported finding an RNA molecule that could accurately&nbsp;— but crucially not perfectly&nbsp;— reproduce itself in the laboratory.<ref>[https://www.pnas.org/doi/10.1073/pnas.2321592121 RNA-catalyzed evolution of catalytic RNA] by Nikolaos Papastavrou, David P. Horning & Gerald F. Joyce (2024) ''PNAS'' 121(11):e2321592121. doi:10.1073/pnas.2321592121.</ref> The crucial slight imperfections allowed for the possibility for mutation and hence adaptation.<ref>[https://www.washingtonpost.com/science/2024/03/09/origin-of-life-rna-world ‘Monumental’ experiment suggests how life on Earth may have started] by Mark Johnson (March 9, 2024 at 8:00 a.m. EST) ''The Washington Post''.</ref>

==See also==
*[[Abiogenesis]]
*[[Origin of life]]

==External links==
# [http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/A/AbioticSynthesis.html#An_RNA_Beginning The Origin of Life:  Abiotic Synthesis of Organic Molecules (An RNA Beginning?)] (intro to the RNA world and ribozymes, RNA as an enzyme)
# [http://www.math.auckland.ac.nz/~king/Preprints/Elechem.htm  Did Membrane Electrochemistry Precede Translation?] (shows structures of various RNA-containing cofactors)
# [http://www.yale.edu/breaker/deoxyribozymes.htm Deoxyribozymes] (DNA as an enzyme)
# [http://www.yale.edu/breaker/riboswitch.htm Riboswitches] (RNA as a gene regulator)

==Sources==
# Leipe DD, Aravind L, Koonin EV., "Did DNA replication evolve twice independently?", ''Nucleic Acids Res.'' 1999 Sep 1;27(17):3389-401., at [http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10446225&dopt=Abstract this PubMed entry].

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