RNA world hypothesis

The RNA world hypothesis is a theory which proposes that a world filled with RNA (ribonucleic acid) based life predates current DNA (deoxyribonucleic acid) based life. RNA, which can store information like DNA and catalyze reactions like proteins (enzymes), may have supported cellular or pre-cellular life. Some theories 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 the evolutionary remnant of the RNA world.

History
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. However, the idea of independent RNA life is older and can be found in Carl Woese's The Genetic Code. 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. Such nucleic acids are sometimes more easily produced and/or polymerized under pre-biotic conditions. Suggestions for such nucleic acids include PNA, TNA or GNA .

RNA as an enzyme
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%, which would mean it would make an exact copy of an RNA molecule as long as itself in one of every eight copies.
 * The ability to catalyze simple chemical reactions which will enhance the creation of molecules which are building blocks of RNA molecules. Relatively short RNA molecule with such abilities have been artificially formed in the lab.
 * The ability to form 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 . It has also been suggested that amino acids may have initially been complexed with RNA molecules as cofactors enhancing or divesifying 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.

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
The major difference 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 (ie. 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 to DNA.

RNA also uses a different set of bases to DNA - adenine, guanine, cytosine and uracil instead of adenine, guanine, cytosine and thymine. Chemically uracil is similar to thymine, although uses less energy to produce. 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
Storage of large amounts of information in RNA is not easy. The chemical properties of RNA make large RNA molecules inherently fragile and 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. These limitations do not make use of RNA as an information store 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.

Support
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 (an enzyme made of ribonucleic acid). Because it can reproduce on its own, performing the tasks of both DNA and proteins (enzymes), RNA is believed 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, notably those of Joan Oro. Experiments with basic ribozymes, like the viral RNA Q-beta, have shown that simple self-replicating RNA structures can withstand even strong selective pressures (e.g., opposite-chirality chain terminators) (The Basics of Selection (London: Springer, 1997)).

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 break down of RNA (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.

Difficulties
The base cytosine does not have a plausible prebiotic simulation method because it easily undergoes hydrolysis.

Prebiotic simulations making nucleotides have conditions incompatible with those for making sugars (lots of formaldehyde). So they must somehow be synthesized, then brought together. However, they do not react in water. Anhydrous reactions bind with purines, but only 8% of them bind with the correct carbon atom on the sugar bound to the correct nitrogen atom on the base. Pyrimidines, however, do not react with ribose, even anhydrously.

Then phosphate must be introduced, but in nature phosphate in solution is extremely rare because it is so readily precipitated. After being introduced, the phosphate must combine with the nucleoside and the correct hydroxyl must be phosphorylated, in order to create a nucleotide.

For the nucleotides to form RNA, they must be activated themselves (meaning that they must be combined with two more phosphate groups, as in adenosine triphosphate). Activated purine nucleotides form small chains on a pre-existing template of all-pyrimidine RNA. However, this does not happen in reverse because the pyrimidine nucleotides do not stack well.

Additionally, the ribose must all be the same enantiomer, because any nucleotides of the wrong chirality act as chain terminators.

A.G. Cairns-Smith in 1982 criticized writers for exaggerating the implications of the Miller-Urey experiment. He argued that the experiment showed, not the possibility that nucleic acids preceded life, but its implausibility. He claimed that the process of constructing nucleic acids would require 18 distinct conditions and events that would have to occur continually over millions of years in order to build up the required quantities.

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.

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 (peptide-bonding). These amino acids could then assist with RNA synthesis, giving those RNA chains that could serve as ribozymes the selective advantage. Eventually DNA, lipids, carbohydrates, and all sorts of other chemicals were recruited into life. This led to the first prokaryotic cells, and eventually to life as we know it.

Further developments
Patrick Forterre has been working on a controversial 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.

Alternative theories
As mentioned above, a different verion of the same theory is "pre-RNA world", where a different nucleic acid is proposed to pre-date RNA. A proposed alternative is the peptide nucleic acid, PNA. PNA is more stable than RNA and appears to be more readily synthesized in prebiotic conditions, especially where the synthesis of ribose and adding phosphate groups are problematic, because it contains neither. Threose nucleic acid (TNA) has also been proposed as a starting point, as has Glycol nucleic acid GNA.

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

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 Eucaryotes in the maintenance of telomeres in the telomerase reaction.