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RNA world hypothesis

The RNA world hypothesis proposes that a world filled with life based on ribonucleic acid (RNA) predates the current world of life based on deoxyribonucleic acid (DNA) and protein. RNA, which can both store information like DNA and act as an enzyme like proteins, may have supported cellular or pre-cellular life. Some hypotheses as to the origin of life present RNA-based catalysis and information storage as the first step in the evolution of cellular life.

The RNA world is proposed to have evolved into the DNA and protein world of today. DNA, through its greater chemical stability, took over the role of data storage while protein, which is more flexible in catalysis through the great variety of amino acids, became the specialized catalytic molecules. The RNA world hypothesis suggests that RNA in modern cells, in particular rRNA (RNA in the ribosome which catalyzes protein production), is an evolutionary remnant of the RNA world.


The phrase "RNA World" was first used by Nobel laureate Walter Gilbert in 1986, in a commentary on recent observations of the catalytic properties of various forms of RNA.[1] However, the idea of independent RNA life is older and can be found in Carl Woese's 1968 book The Genetic Code.[2] In 1963, the molecular biologist Alexander Rich, of the Massachusetts Institute of Technology, had posited much the same idea in an article he contributed to a volume issued in honor of Nobel-laureate physiologist Albert Szent-Györgyi.

Properties of RNA

The properties of RNA make the idea of the RNA world hypothesis conceptually possible, although its plausibility as an explanation for the origin of life is debated. RNA is known to form efficient catalysts and its similarity to DNA makes its ability to store information clear.

A slightly different version of the hypothesis is that a different type of nucleic acid, termed pre-RNA, was the first one to emerge as a self-reproducing molecule, to be replaced by RNA only later. This claim has been made due to (to date) failed attempts to efficiently synthesize activated RNA nucleotides which have the capability to undergo self-polymerization. Suggestions for 'simpler' nucleic acids include Peptide nucleic acid (PNA), Threose nucleic acid (TNA) or Glycerol nucleic acid (GNA).[3][4] Despite their structural simplicity and possessing properties as good or greater than RNA, the chemically plausible generation of such monomers or oligomers under potentially prebiotic conditions has yet to be demonstrated.[5]

RNA as an enzyme
Further information: ribozyme

RNA enzymes, or ribozymes, are possible although not common in today's DNA-based life. However ribozymes play vital roles; ribozymes are essential components of the ribosome, which is vital for protein synthesis. Many ribozyme functions are possible: Nature widely uses RNA self-splicing and directed evolution has created ribozymes with a variety of activities.

Among the enzymatic properties important for the beginning of life are:

* The ability to self-duplicate, or duplicate other RNA molecules. Relatively short RNA molecules that can duplicate others have been artificially produced in the lab. The shortest was 165-base long, though it has been estimated that only part of the bases were crucial for this function. One version, 189-base long, had fidelity of 98.9%,[6] which would mean it would make an exact copy of an RNA molecule as long as itself in one of every eight copies. This 189 base pair ribozyme could polymerize a template of at most 14 nucleotides in length, which is too short for replication, but a promising lead for further investigation. The longest primer extension by a ribozyme polymerase was 20 bases.[7]
* The ability to catalyze simple chemical reactions which would enhance the creation of molecules which are building blocks of RNA molecules—i.e., a strand of RNA which would make creating more strands of RNA easier. Relatively short RNA molecules with such abilities have been artificially formed in the lab.[8][9]
* The ability to catalyse the formation of peptide bonds, in order to produce short peptides, or—eventually—full proteins. This is done in modern cells by ribosomes, a complex of two large RNA molecules known as rRNA and many proteins. The two rRNA molecules are thought to be responsible for its enzymatic activity. A much shorter RNA molecule has been formed in lab with the ability to form peptide bonds, and it has been suggested that rRNA has evolved from a similar molecule.[10] It has also been suggested that amino acids may have initially been complexed with RNA molecules as cofactors enhancing or diversifying their enzymatic capabilities, before evolving to the more complex peptides. mRNA may have evolved from such RNA molecules, and tRNA from RNA molecules which had catalyzed amino acid transfer to them.[11]

RNA in information storage

RNA is a very similar molecule to DNA, and only has two chemical differences. The overall structure of RNA and DNA are immensely similar—one strand of DNA and one of RNA can bind to form a double helical structure. This makes the storage of information in RNA possible in a very similar way to the storage of information in DNA.

Comparison of DNA and RNA structure
Main articles: RNA and DNA

The major difference between RNA and DNA is the presence of a hydroxyl group at the 2'-position of the ribose sugar in RNA. This group makes the molecule less stable—in flexible regions of an RNA molecule (i.e., where not constrained in a double helix), it can chemically attack the adjacent phosphodiester bond to cleave the phosphodiester backbone. The hydroxyl group also forces the ribose into the C3'-endo sugar conformation unlike the C2'-endo conformation of the deoxyribose sugar in DNA. This forces a RNA double helix into a slightly different conformation than B-DNA, resembling A-DNA more closely.

RNA also uses a different set of bases than DNA—adenine, guanine, cytosine and uracil, instead of adenine, guanine, cytosine and thymine. Chemically, uracil is similar to thymine, differing only by a methyl group, and its production requires less energy. In terms of base pairing this has no effect, adenine will readily bind uracil or thymine. Uracil is, however, one product of damage to cytosine making RNA particularly susceptible to mutations which replace a GC base pair with a GU (wobble) or AU base pair.

Limitations of information storage in RNA

Storing large amounts of information in RNA is not easy. The chemical properties of RNA make large RNA molecules inherently fragile, and they can easily be broken down into their constituent nucleotides through hydrolysis. The aromatic bases also absorb strongly in the ultraviolet region, and would have been susceptible to damage and breakdown by background radiation.[12][13] These limitations do not make use of RNA as an information storage system impossible, simply energy intensive (to repair or replace damaged RNA molecules) and mutation prone. While this makes it unsuitable for current 'DNA optimised' life, it may have been suitable for primitive life.

RNA as a regulator
Main article: riboswitch

Riboswitches have been found to act as regulators of gene expression, particularly in bacteria, but also in plants and archaea. It has been suggested that these originated in an RNA based world.[14]

Support and difficulties

The RNA World hypothesis is supported by RNA's ability to store, transmit, and duplicate genetic information, as DNA does. RNA can also act as a ribozyme, a special type of enzyme. Because it can reproduce on its own, performing the tasks of both DNA and proteins (enzymes), RNA is believed[by whom?] to have once been capable of independent life. Further, while nucleotides were not found in Miller-Urey's origins of life experiments, they were found by others' simulations[citation needed]; the purine base known as adenine is merely a pentamer of hydrogen cyanide. Experiments with basic ribozymes, like the viral RNA Qβ, have shown that simple self-replicating RNA structures can withstand even strong selective pressures (e.g., opposite-chirality chain terminators).[15]

Additionally, in the past a given RNA molecule might have survived longer than it can today. Ultraviolet light can cause RNA to polymerize while at the same time breaking down other types of organic molecules that could have the potential of catalyzing the breakdown of RNA (called ribonucleases), suggesting that RNA may have been a relatively common substance on early Earth. This aspect of the theory is still untested and is based on a constant concentration of sugar-phosphate molecules.

Since there were no known chemical pathways for the abiogenic synthesis of nucleotides from pyrimidine nucleobases cytosine and uracil under prebiotic conditions, it is thought by some that nucleic acids did not contain these nucleobases seen in life's nucleic acids.[16] The nucleoside cytosine has a half-life in isolation of 19 days at 100 °C (212 °F) and 17,000 years in freezing water, which has been argued to be too short on the geologic time scale for accumulation.[17] Others have questioned whether ribose and other backbone sugars could be stable enough to be found in the original genetic material,[18] and have raised the issue that ribose must all be the same enantiomer as any nucleotide of the wrong chirality acts as a chain terminator.[19]

Pyrimidine ribonucleosides and their respective nucleotides have been prebiotically synthesised by a sequence of reactions which by-pass the free sugars, and is assembled in a stepwise fashion by going against the dogma that nitrogenous and oxygenous chemistries should be avoided. In a series of publications, The Sutherland Group at the School of Chemistry, University of Manchester have demonstrated high yielding routes to cytidine and uridine ribonucleotides built from small 2 and 3 carbon fragments such as glycolaldehyde, glyceraldehyde or glyceraldehyde-3-phosphate, cyanamide and cyanoacetylene. One of the steps in this sequence allows the isolation of enantiopure ribose aminooxazoline if the enantiomeric excess of glyceraldehyde is 60 % or greater, of possible interest towards biological homochirality.[20] This can be viewed as a prebiotic purification step, where the said compound spontaneously crystallised out from a mixture of the other pentose aminooxazolines. Aminooxazolines can react with cyanoacetylene in a mild and highly efficient manner, controlled by inorganic phosphate, to give the cytidine ribonucleotides. Photoanomerization with UV light allows for inversion about the 1' anomeric centre to give the correct beta stereochemistry, one problem with this chemistry is the selective phosphorylation of alpha-cytidine at the 2' position.[21] However, in 2009 they showed that the same simple building blocks allow access, via phosphate controlled nucleobase elaboration, to 2',3'-cyclic pyrimidine nucleotides directly, which are known to be able to polymerise into RNA.[22] This was hailed as strong evidence for the RNA world.[23] The paper also highlighted the possibility for the photo-sanitization of the pyrimidine-2',3'-cyclic phosphates.[22] A potential weakness of these routes is the generation of enantioenriched glyceraldehyde, or its 3-phosphate derivative (glyceraldehyde prefers to exist as its keto tautomer dihydroxyacetone).[citation needed]

Details of the RNA world

Mechanism for prebiotic RNA synthesis

Nucleotides are the fundamental molecules that combine in series to form RNA. They consist of a nitrogenous base attached to a sugar-phosphate backbone. RNA is made of long stretches of specific nucleotides arranged so that their sequence of bases carries information. The RNA world hypothesis holds that in the primordial soup/primordial sandwich, there existed free-floating nucleotides. These nucleotides regularly formed bonds with one another, which often broke because the change in energy was so low. However, certain sequences of base pairs have catalytic properties that lower the energy of their chain being created, causing them to stay together for longer periods of time. As each chain grew longer, it attracted more matching nucleotides faster, causing chains to now form faster than they were breaking down.

These chains are proposed as the first, primitive forms of life. In an RNA world, different forms of RNA compete with each other for free nucleotides and are subject to natural selection. The most efficient molecules of RNA, the ones able to efficiently catalyze their own reproduction, survived and evolved, forming modern RNA. Such an RNA enzyme, capable of self replication in about an hour has been identified. It was produced by molecular competition (in vitro evolution) of candidate enzyme mixtures.[24]

Competition between RNA may have favored the emergence of cooperation between different RNA chains, opening the way for the formation of the first proto-cell. Eventually, RNA chains randomly developed with catalytic properties that help amino acids bind together (a process called peptide-bonding). These amino acids could then assist with RNA synthesis, giving those RNA chains that could serve as ribozymes the selective advantage. The ability to catalyze one step in protein synthesis, aminoacylation of RNA, has been demonstrated in a short (five-nucleotide) segment of RNA.[25]

Further developments

Patrick Forterre has been working on a novel hypothesis, that viruses were instrumental in the transition from RNA to DNA and the evolution of Bacteria, Archaea, and Eukaryota. He believes the last common ancestor was RNA-based and evolved RNA viruses. Some of the viruses evolved into DNA viruses to protect their genes from attack. Through the process of viral infection into hosts the three domains of life evolved.[26][27] Another interesting proposal is the idea that RNA synthesis might have been driven by temperature gradients, in the process of thermosynthesis.[28]

Alternative hypotheses

As mentioned above, a different version of the same hypothesis is "Pre-RNA world", where a different nucleic acid is proposed to pre-date RNA.

One of the alternate nucleic acid hypotheses is the PNA world hypothesis involving peptide nucleic acid, PNA. PNA is more stable than RNA, but its ability to be generated under prebiological conditions has yet to be demonstrated experimentally.

Threose nucleic acid (TNA) has also been proposed as a starting point, as has glycol nucleic acid (GNA), and like PNA, also lack experimental evidence for their respective abiogenesis.

A different—or complementary—alternative to the assembly of RNA is proposed in the PAH world hypothesis.

The iron-sulfur world theory proposes that simple metabolic processes developed before genetic materials did, and these energy-producing cycles catalyzed the production of genes.

Yet another alternative theory to the RNA world hypothesis is the panspermia hypothesis. It discusses the possibility that the earliest life on this planet was carried here from somewhere else in the galaxy, possibly on meteorites similar to the Murchison meteorite.[29] This does not invalidate the concept of an RNA world, but posits that this world was not Earth but rather another, probably older planet.

Implications of the RNA world

The RNA world hypothesis, if true, has important implications for the very definition of life. For the majority of the time following the elucidation of the structure of DNA by Watson and Crick, life was considered as being largely defined in terms of DNA and proteins: DNA and proteins seemed to be the dominant macromolecules in the living cell, with RNA serving only to aid in creating proteins from the DNA blueprint.

The RNA world hypothesis places RNA at center-stage when life originated. This has been accompanied by many studies in the last ten years demonstrating important aspects of RNA function that were not previously known, and support the idea of a critical role for RNA in the functionality of life. In 2001, the RNA world hypothesis was given a major boost with the deciphering of the 3-dimensional structure of the ribosome, which revealed the key catalytic sites of ribosomes to be composed of RNA and for the proteins to hold no major structural role, and be of peripheral functional importance. Specifically, the formation of the peptide bond, the reaction that binds amino acids together into proteins, is now known to be catalyzed by an adenine residue in the rRNA: the ribosome is a ribozyme. This finding suggests that RNA molecules were most likely capable of generating the first proteins. Other interesting discoveries demonstrating a role for RNA beyond a simple message or transfer molecule include the importance of small nuclear ribonucleoproteins (SnRNPs) in the processing of pre-mRNA and RNA editing and reverse transcription from RNA in Eukaryotes in the maintenance of telomeres in the telomerase reaction.

See also

* Abiogenesis
* Autocatalytic set
* The Major Transitions in Evolution
* Panspermia


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14. ^ Switching the light on plant riboswitches. Samuel Bocobza and Asaph Aharoni Trends in Plant Science Volume 13, Issue 10, October 2008, Pages 526-533 doi:10.1016/j.tplants.2008.07.004
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Further reading

* Cairns-Smith, A. G. (1993). Genetic Takeover: And the Mineral Origins of Life. Cambridge University Press. ISBN 0-521-23312-7.
* Orgel, L. E. (October 1994). "The origin of life on the Earth". Scientific American 271: 76–83. doi:10.1038/scientificamerican1094-76.
* Woolfson, Adrian (September 2000). Life Without Genes. London: Flamingo. ISBN 978-0006548744.
* Vlassov, Alexander V.; Kazakov, Sergei A.; Johnston, Brian H.; Landweber, Laura F. (July 2005). "The RNA World on Ice: A New Scenario for the Emergence of RNA Information". Journal of Molecular Evolution 61 (2): 264–273. doi:10.1007/s00239-004-0362-7. PMID 16044244.

External links

* "The RNA world" (2001) by Sidney Altman, on the Nobel prize website
* "Exploring the new RNA world" (2004) by Thomas R. Cech, on the Nobel prize website
* "The Formation of the RNA World" by James P. Ferris
* "Exploring Life's Origins: a Virtual Exhibit"
* http://www.hhmi.org/bulletin/pdf/june2002/RNA.pdf HHMI bulletin
* http://www.panspermia.org/rnaworld.htm

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