RNA world

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A comparison of RNA (left) with DNA (right), showing the helices and nucleobases each employs

The RNA world refers to the self-replicating ribonucleic acid (RNA) molecules hypothesised to have been the precursors to all current life on Earth.^[1][2][3] The hypothesis that current life on Earth descends from an RNA world is widely accepted,^[4][5] and is supported by several lines of evidence including how ephemeral RNA was protected on the early earth.^[6] Alternative chemical paths to life have been proposed,^[7] and RNA-based life may not have been the first life to exist.^[8][9]

The RNA world would have eventually been replaced by the DNA-RNA-protein world of today, likely through an intermediate stage of ribonucleoprotein enzymes such as the ribosome and ribozymes, since it is argued that proteins large enough to self-fold and have useful activities would only have come about after RNA was available to catalyze peptide ligation or amino acid polymerization.^[9] DNA is thought to have taken over the role of data storage due to its increased stability,^[10] while proteins, through a greater variety of monomers (amino acids), replaced RNA's role in specialized biocatalysis.

The RNA world hypothesis is supported by many independent lines of evidence, such as the observations that RNA is central to the translation process and that small RNAs can catalyze all of the chemical group and information transfers required for life.^[9][11] The structure of the ribosome has been called the "smoking gun," as it showed that the ribosome is a ribozyme, with a central core of RNA and no amino acid side chains within 18 angstroms of the active site where peptide bond formation is catalyzed.^[8] Many of the most critical components of cells (those that evolve the slowest) are composed mostly or entirely of RNA. Also, many critical cofactors (ATP, Acetyl-CoA, NADH, etc.) are either nucleotides or substances clearly related to them. This would mean that the RNA and nucleotide cofactors in modern cells could be an evolutionary remnant of an RNA-based enzymatic system that preceded the protein-based one seen in all extant life.

History

One of the challenges in studying abiogenesis is that the system of reproduction and metabolism utilized by all extant life involves three distinct types of interdependent macromolecules (DNA, RNA, and protein). This suggests that life could not have arisen in its current form, and mechanisms have then been sought whereby the current system might have arisen from a simpler precursor system. The concept of RNA as a primordial molecule^[9] can be found in papers by Francis Crick^[12] and Leslie Orgel,^[13] as well as in Carl Woese's 1967 book The Genetic Code.^[14] In 1962 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.^[15] Hans Kuhn in 1972 laid out a possible process by which the modern genetic system might have arisen from a nucleotide-based precursor, and this led Harold White in 1976 to observe that many of the cofactors essential for enzymatic function are either nucleotides or could have been derived from nucleotides. He proposed that these nucleotide cofactors represent "fossils of nucleic acid enzymes".^[16] The phrase "RNA World" was first used by Nobel laureate Walter Gilbert in 1986, in a commentary on how recent observations of the catalytic properties of various forms of RNA fit with this hypothesis.^[17]

Properties of RNA

The properties of RNA make the idea of the RNA world hypothesis conceptually plausible, though its general acceptance as an explanation for the origin of life requires further evidence.^[15] RNA is known to form efficient catalysts and its similarity to DNA makes clear its ability to store information. Opinions differ, however, as to whether RNA constituted the first autonomous self-replicating system or was a derivative of a still-earlier system.^[9] One 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. On the other hand, the recent finding that activated pyrimidine ribonucleotides can be synthesized under plausible prebiotic conditions^[18] means that it is premature to dismiss the RNA-first scenarios.^[9] Suggestions for 'simple' pre-RNA nucleic acids have included peptide nucleic acid (PNA), threose nucleic acid (TNA) or glycol nucleic acid (GNA).^[19][20] Despite their structural simplicity and possession of properties comparable with RNA, the chemically plausible generation of "simpler" nucleic acids under prebiotic conditions has yet to be demonstrated.^[21]

RNA as an enzyme

RNA enzymes, or ribozymes, are found in today's DNA-based life and could be examples of living fossils. Ribozymes play vital roles, such as those in the ribosome, which is vital for protein synthesis. Many other ribozyme functions exist; for example, the hammerhead ribozyme performs self-cleavage^[22] and an RNA polymerase ribozyme can synthesize a short RNA strand from a primed RNA template.^[23]

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

• Self-replication. The ability to self-replicate, or synthesize other RNA molecules; relatively short RNA molecules that can synthesize others have been artificially produced in the lab. The shortest was 165-bases long, though it has been estimated that only part of the molecule was crucial for this function. One version, 189-bases long, had an error rate of just 1.1% per nucleotide when synthesizing an 11 nucleotide long RNA strand from primed template strands.^[24] This 189 base pair ribozyme could polymerize a template of at most 14 nucleotides in length, which is too short for self replication, but a potential lead for further investigation. The longest primer extension performed by a ribozyme polymerase was 20 bases.^[25] In 2016, researchers reported the use of in vitro evolution to improve dramatically the activity and generality of an RNA polymerase ribozyme by selecting variants that can synthesize functional RNA molecules from an RNA template. Each RNA polymerase ribozyme was engineered to remain linked to its new, synthesized RNA strand, this allowed the team to isolate successful polymerases. The isolated RNA polymerases were again used for another round of evolution. After several rounds of evolution, they obtained one RNA polymerase ribozyme called 24-3 that was able to copy almost any other RNA, from small catalysts to long RNA based enzymes. Particular RNAs were amplified up to 10,000 times, a first RNA version of the polymerase chain reaction (PCR). The RNA polymerase is not yet able to make copies of itself.^[26]
• Catalysis. The ability to catalyze simple chemical reactions—which would enhance creation of molecules that 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.^[27][28] A recent study showed that almost any nucleic acid can evolve into a catalytic sequence under appropriate selection. For instance, an arbitrarily chosen 50-nucleotide DNA fragment encoding for the Bos taurus (cattle) albumin mRNA was subjected to test-tube evolution to derive a catalytic DNA (DNAzyme) with RNA-cleavage activity. After only a few weeks, a DNAzyme with significant catalytic activity had evolved.^[29] In general, DNA is much more chemically inert than RNA and hence much more resistant to obtaining catalytic properties. If in vitro evolution works for DNA it will happen much more easily with RNA.
• Amino acid-RNA ligation. The ability to conjugate an amino acid to the 3'-end of an RNA in order to use its chemical groups or provide a long-branched aliphatic side-chain.^[30]
• Peptide bond formation. The ability to catalyse the formation of peptide bonds between amino acids to produce short peptides or longer proteins. This is done in modern cells by ribosomes, a complex of several RNA molecules known as rRNA together with many proteins. The rRNA molecules are thought responsible for its enzymatic activity, as no amino acid molecules lie within 18Å of the enzyme's active site,^[15] and, when the majority of the amino acids in the ribosome were stringently removed, the resulting ribosome retained its full peptidyl transferase activity, fully able to catalyze the formation of peptide bonds between amino acids.^[31] A much shorter RNA molecule has been synthesized in the laboratory with the ability to form peptide bonds, and it has been suggested that rRNA has evolved from a similar molecule.^[32] It has also been suggested that amino acids may have initially been involved with RNA molecules as cofactors enhancing or diversifying their enzymatic capabilities, before evolving to more complex peptides. Similarly, tRNA is suggested to have evolved from RNA molecules that began to catalyze amino acid transfer.^[33]

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. However RNA is less stable.

The major difference between RNA and DNA is the presence of a hydroxyl group at the 2'-position.

Comparison of DNA and RNA structure

The major difference between RNA and DNA is the presence of a hydroxyl group at the 2'-position of the ribose sugar in RNA (illustration, right).^[15] This group makes the molecule less stable because when not constrained in a double helix, the 2' hydroxyl 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 an RNA double helix to change from a B-DNA structure to one more closely resembling A-DNA.
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.^[34] In terms of base pairing, this has no effect. Adenine readily binds uracil or thymine. Uracil is, however, one product of damage to cytosine that makes RNA particularly susceptible to mutations that can replace a GC base pair with a GU (wobble) or AU base pair.

RNA is thought to have preceded DNA, because of their ordering in the biosynthetic pathways. The deoxyribonucleotides used to make DNA are made from ribonucleotides, the building blocks of RNA, by removing the 2'-hydroxyl group. As a consequence a cell must have the ability to make RNA before it can make DNA.

Limitations of information storage in RNA

The chemical properties of RNA make large RNA molecules inherently fragile, and they can easily be broken down into their constituent nucleotides through hydrolysis.^[35][36] 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 prone to mutation. While this makes it unsuitable for current 'DNA optimised' life, it may have been acceptable for more primitive life.

RNA as a regulator

Riboswitches have been found to act as regulators of gene expression, particularly in bacteria, but also in plants and archaea. Riboswitches alter their secondary structure in response to the binding of a metabolite. This change in structure can result in the formation or disruption of a terminator, truncating or permitting transcription respectively.^[37] Alternatively, riboswitches may bind or occlude the Shine-Dalgarno sequence, affecting translation.^[38] It has been suggested that these originated in an RNA-based world.^[39] In addition, RNA thermometers regulate gene expression in response to temperature changes.^[40]

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 act as a ribozyme, a special type of enzyme. Because it can perform the tasks of both DNA and enzymes, RNA is believed to have once been capable of supporting independent life forms.^[15] Some viruses use RNA as their genetic material, rather than DNA.^[41] Further, while nucleotides were not found in experiments based on Miller-Urey experiment, their formation in prebiotically plausible conditions has now been reported, as noted above;^[18] the purine base known as adenine is merely a pentamer of hydrogen cyanide. Experiments with basic ribozymes, like Bacteriophage Qβ RNA, have shown that simple self-replicating RNA structures can withstand even strong selective pressures (e.g., opposite-chirality chain terminators).^[42]

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.^[43] 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 some argue is too short on the geologic time scale for accumulation.^[44] Others have questioned whether ribose and other backbone sugars could be stable enough to find in the original genetic material,^[45] and have raised the issue that all ribose molecules would have had to be the same enantiomer, as any nucleotide of the wrong chirality acts as a chain terminator.^[46]

Pyrimidine ribonucleosides and their respective nucleotides have been prebiotically synthesised by a sequence of reactions that by-pass free sugars and assemble in a stepwise fashion by including nitrogenous and oxygenous chemistries. In a series of publications, John Sutherland and his team 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.^[47] 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.^[48] 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.^[18] Organic chemist Donna Blackmond described this finding as "strong evidence" in favour of the RNA world.^[49] However, John Sutherland said that while his team's work suggests that nucleic acids played an early and central role in the origin of life, it did not necessarily support the RNA world hypothesis in the strict sense, which he described as a "restrictive, hypothetical arrangement".^[50]

The Sutherland group's 2009 paper also highlighted the possibility for the photo-sanitization of the pyrimidine-2',3'-cyclic phosphates.^[18] 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]}

On August 8, 2011, a report, based on NASA studies with meteorites found on Earth, was published suggesting building blocks of RNA (adenine, guanine and related organic molecules) may have been formed extraterrestrially in outer space.^[51][52][53] On August 29, 2012, astronomers at Copenhagen University reported the detection of a specific sugar molecule, glycolaldehyde, in a distant star system. The molecule was found around the protostellar binary IRAS 16293-2422, which is located 400 light years from Earth.^[54][55] Because glycolaldehyde is needed to form RNA, this finding suggests that complex organic molecules may form in stellar systems prior to the formation of planets, eventually arriving on young planets early in their formation.^[56]

"Molecular biologist's dream"

"Molecular biologist's dream" is a phrase coined by Gerald Joyce and Leslie Orgel to refer to the problem of emergence of self-replicating RNA molecules, as any movement towards an RNA world on a properly modeled prebiotic early Earth would have been continuously suppressed by destructive reactions.^[57] It was noted that many of the steps needed for the nucleotides formation do not proceed efficiently in prebiotic conditions.^[58] Joyce and Orgel specifically referred the molecular biologist's dream to "a magic catalyst" that could "convert the activated nucleotides to a random ensemble of polynucleotide sequences, a subset of which had the ability to replicate".^[57]

Joyce and Orgel further argued that nucleotides cannot link unless there is some activation of the phosphate group, whereas the only effective activating groups for this are "totally implausible in any prebiotic scenario", particularly adenosine triphosphate.^[57] According to Joyce and Orgel, in case of the phosphate group activation, the basic polymer product would have 5',5'-pyrophosphate linkages, while the 3',5'-phosphodiester linkages, which are present in all known RNA, would be much less abundant.^[57] The associated molecules would have been also prone to addition of incorrect nucleotides or to reactions with numerous other substances likely to have been present.^[57] The RNA molecules would have been also continuously degraded by such destructive process as spontaneous hydrolysis, present on the early Earth.^[57] Joyce and Orgel proposed to reject "the myth of a self-replicating RNA molecule that arose de novo from a soup of random polynucleotides"^{[57][citation needed][unreliable source?]} and hypothesised a scenario where the prebiotic processes furnish pools of enantiopure beta-D-ribonucleosides.^[59] In a later paper, Joyce describes "The myth of a small RNA molecule that arises de novo and can replicate efficiently and with high fidelity under plausible prebiotic conditions" as a strawman.^[60]

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 (or 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, enabling 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 have been proposed by some as the first, primitive forms of life.^[61] In an RNA world, different sets of RNA strands would have had different replication outputs, which would have increased or decreased their frequency in the population, i.e. natural selection. As the fittest sets of RNA molecules expanded their numbers, novel catalytic properties added by mutation, which benefitted their persistence and expansion, could accumulate in the population. Such an autocatalytic set of ribozymes, capable of self replication in about an hour, has been identified. It was produced by molecular competition (in vitro evolution) of candidate enzyme mixtures.^[62]

Competition between RNA may have favored the emergence of cooperation between different RNA chains, opening the way for the formation of the first protocell. Eventually, RNA chains 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.^[63]

One of the problems with the RNA world hypothesis is to discover the pathway by which RNA became upgraded to the DNA system. Geoffrey Diemer and Ken Stedman at Portland State University in Oregon, may have found a solution. While conducting a survey of viruses in a hot acidic lake in Lassen Volcanic National Park, California, they uncovered evidence that a simple DNA virus had acquired a gene from a completely unrelated RNA-based virus. Virologist Luis Villareal of the University of California Irvine also suggests that viruses capable of converting an RNA-based gene into DNA and then incorporating it into a more complex DNA-based genome might have been common in the Virus world during the RNA to DNA transition some 4 billion years ago.^[64][65] This finding bolsters the argument for the transfer of information from the RNA world to the emerging DNA world before the emergence of the Last Universal Common Ancestor. From the research, the diversity of this virus world is still with us.

In March 2015, NASA scientists reported that, for the first time, complex DNA and RNA organic compounds of life, including uracil, cytosine and thymine, have been formed in the laboratory under conditions found only in outer space, using starting chemicals, like pyrimidine, found in meteorites. Pyrimidine, like polycyclic aromatic hydrocarbons (PAHs), the most carbon-rich chemical found in the Universe, may have been formed in giant red stars or in interstellar dust and gas clouds, according to the scientists.^[66]

Viroids

Additional evidence supporting the concept of an RNA world has resulted from research on viroids, the first representatives of a novel domain of "subviral pathogens."^[67][68] Viroids are mostly plant pathogens, which consist of short stretches (a few hundred nucleobases) of highly complementary, circular, single-stranded, and non-coding RNA without a protein coat. Compared with other infectious plant pathogens, viroids are extremely small in size, ranging from 246 to 467 nucleobases. In comparison, the genome of the smallest known viruses capable of causing an infection are about 2,000 nucleobases long.^[69]

In 1989, Diener proposed that, based on their characteristic properties, viroids are more plausible "living relics" of the RNA world than are introns or other RNAs then so considered.^[70] If so, viroids have attained potential significance beyond plant pathology to evolutionary biology, by representing the most plausible macromolecules known capable of explaining crucial intermediate steps in the evolution of life from inanimate matter (see: abiogenesis).

Apparently, Diener's hypothesis lay dormant until 2014, when Flores et al. published a review paper, in which Diener's evidence supporting his hypothesis was summarized.^[71] In the same year, a New York Times science writer published a popularized version of Diener's proposal, in which, however, he mistakenly credited Flores et al. with the hypothesis' original conception.^[72]

Pertinent viroid properties listed in 1989 are:

1. their small size, imposed by error-prone replication;
2. their high guanine and cytosine content, which increases stability and replication fidelity;
3. their circular structure, which assures complete replication without genomic tags;
4. existence of structural periodicity, which permits modular assembly into enlarged genomes;
5. their lack of protein-coding ability, consistent with a ribosome-free habitat; and
6. replication mediated in some by ribozymes—the fingerprint of the RNA world.^[71]

The existence, in extant cells, of RNAs with molecular properties predicted for RNAs of the RNA World constitutes an additional argument supporting the RNA World hypothesis.

Origin of sex

Eigen et al.^[73] and Woese^[74] proposed that the genomes of early protocells were composed of single-stranded RNA, and that individual genes corresponded to separate RNA segments, rather than being linked end-to-end as in present-day DNA genomes. A protocell that was haploid (one copy of each RNA gene) would be vulnerable to damage, since a single lesion in any RNA segment would be potentially lethal to the protocell (e.g. by blocking replication or inhibiting the function of an essential gene).

Vulnerability to damage could be reduced by maintaining two or more copies of each RNA segment in each protocell, i.e. by maintaining diploidy or polyploidy. Genome redundancy would allow a damaged RNA segment to be replaced by an additional replication of its homolog. However, for such a simple organism, the proportion of available resources tied up in the genetic material would be a large fraction of the total resource budget. Under limited resource conditions, the protocell reproductive rate would likely be inversely related to ploidy number. The protocell's fitness would be reduced by the costs of redundancy. Consequently, coping with damaged RNA genes while minimizing the costs of redundancy would likely have been a fundamental problem for early protocells.

A cost-benefit analysis was carried out in which the costs of maintaining redundancy were balanced against the costs of genome damage.^[75] This analysis led to the conclusion that, under a wide range of circumstances, the selected strategy would be for each protocell to be haploid, but to periodically fuse with another haploid protocell to form a transient diploid. The retention of the haploid state maximizes the growth rate. The periodic fusions permit mutual reactivation of otherwise lethally damaged protocells. If at least one damage-free copy of each RNA gene is present in the transient diploid, viable progeny can be formed. For two, rather than one, viable daughter cells to be produced would require an extra replication of the intact RNA gene homologous to any RNA gene that had been damaged prior to the division of the fused protocell. The cycle of haploid reproduction, with occasional fusion to a transient diploid state, followed by splitting to the haploid state, can be considered to be the sexual cycle in its most primitive form.^[75][76] In the absence of this sexual cycle, haploid protocells with damage in an essential RNA gene would simply die.

This model for the early sexual cycle is hypothetical, but it is very similar to the known sexual behavior of the segmented RNA viruses, which are among the simplest organisms known. Influenza virus, whose genome consists of 8 physically separated single-stranded RNA segments,^[77] is an example of this type of virus. In segmented RNA viruses, “mating” can occur when a host cell is infected by at least two virus particles. If these viruses each contain an RNA segment with a lethal damage, multiple infection can lead to reactivation providing that at least one undamaged copy of each virus gene is present in the infected cell. This phenomenon is known as “multiplicity reactivation”. Multiplicity reactivation has been reported to occur in influenza virus infections after induction of RNA damage by UV-irradiation,^[78] and ionizing radiation.^[79]

Further developments

Patrick Forterre has been working on a novel hypothesis, called "three viruses, three domains":^[80] 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 (specifically, the "last universal cellular ancestor")^[80] 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.^[80][81] Another interesting proposal is the idea that RNA synthesis might have been driven by temperature gradients, in the process of thermosynthesis.^[82] Single nucleotides have been shown to catalyze organic reactions.^[83]

Steven Benner has argued that chemical conditions on the planet Mars, such as the presence of boron, molybdenum and oxygen, may have been better for initially producing RNA molecules than those on Earth. If so, life-suitable molecules, originating on Mars, may have later migrated to Earth via panspermia or similar process.^[2][3]

Alternative hypotheses

The hypothesized existence of an RNA world does not exclude a "Pre-RNA world", where a metabolic system based on a different nucleic acid is proposed to pre-date RNA. A candidate nucleic acid is peptide nucleic acid (PNA), which uses simple peptide bonds to link nucleobases.^[84] 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.
An alternative — or complementary — theory of RNA origin is proposed in the PAH world hypothesis, whereby polycyclic aromatic hydrocarbons (PAHs) mediate the synthesis of RNA molecules.^[85] PAHs are the most common and abundant of the known polyatomic molecules in the visible Universe, and are a likely constituent of the primordial sea.^[86] PAHs, along with fullerenes (also implicated in the origin of life),^[87] have been recently detected in nebulae.^[88]

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.

Some of the difficulties of producing the precursors on earth are bypassed by another alternative or complementary theory for their origin, panspermia. 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.^[89] This does not invalidate the concept of an RNA world, but posits that this world or its precursors originated not on Earth but rather another, probably older, planet.

There are hypotheses that are in direct conflict to the RNA world hypothesis. The relative chemical complexity of the nucleotide and the unlikelihood of it spontaneously arising, along with the limited number of combinations possible among four base forms, as well as the need for RNA polymers of some length before seeing enzymatic activity, have led some to reject the RNA world hypothesis in favor of a metabolism-first hypothesis, where the chemistry underlying cellular function arose first, along with the ability to replicate and facilitate this metabolism.

RNA-peptide coevolution

Another proposal is that the dual-molecule system we see today, where a nucleotide-based molecule is needed to synthesize protein, and a protein-based molecule is needed to make nucleic acid polymers, represents the original form of life.^[90] This theory is called RNA-peptide coevolution,^[91] or the Peptide-RNA world, and offers a possible explanation for the rapid evolution of high-quality replication in RNA (since proteins are catalysts), with the disadvantage of having to postulate the formation of two complex molecules, an enzyme (from peptides) and a RNA (from nucleotides). In this Peptide-RNA World scenario, RNA would have contained the instructions for life, while peptides (simple protein enzymes) would have accelerated key chemical reactions to carry out those instructions.^[92] The study leaves open the question of exactly how those primitive systems managed to replicate themselves — something neither the RNA World hypothesis nor the Peptide-RNA World theory can yet explain, unless polymerases (enzymes that rapidly assemble the RNA molecule) played a role.^[92]

A research project completed in March 2015 by the Sutherland group found that a network of reactions beginning with hydrogen cyanide and hydrogen sulfide, in streams of water irradiated by UV light, could produce the chemical components of proteins and lipids, alongside those of RNA.^[93][94] The researchers used the term "cyanosulfidic" to describe this network of reactions.^[93]

Implications of the RNA world

The RNA world hypothesis, if true, has important implications for the definition of life. For most of the time that followed Watson and Crick's elucidation of DNA structure in 1953, life was largely defined in terms of DNA and proteins: DNA and proteins seemed the dominant macromolecules in the living cell, with RNA only aiding 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^{[citation needed]} in the last ten years that demonstrate important aspects of RNA function not previously known—and supports the idea of a critical role for RNA in the mechanisms of life. The RNA world hypothesis is supported by the observations that ribosomes are ribozymes: the catalytic site is composed of RNA, and proteins hold no major structural role and are of peripheral functional importance. This was confirmed with the deciphering of the 3-dimensional structure of the ribosome in 2001. Specifically, peptide bond formation, the reaction that binds amino acids together into proteins, is now known to be catalyzed by an adenine residue in the rRNA.

Other interesting discoveries demonstrate a role for RNA beyond a simple message or transfer molecule.^[95] These include the importance of small nuclear ribonucleoproteins (snRNPs) in the processing of pre-mRNA and RNA editing, RNA interference (RNAi), and reverse transcription from RNA in eukaryotes in the maintenance of telomeres in the telomerase reaction.^[96]

Symbiogenesis

From Wikipedia, the free encyclopedia

Internal symbiont: Mitochondrion has a matrix and membranes, like a free-living proteobacterial cell, from which it may derive.

Symbiogenesis, or endosymbiotic theory, is an evolutionary theory of the origin of eukaryotic cells from prokaryotic organisms, first articulated in 1905 and 1910 by the Russian botanist Konstantin Mereschkowski, and advanced and substantiated with microbiological evidence by Lynn Margulis in 1967. It holds that the organelles distinguishing eukaryote cells evolved through symbiosis of individual single-celled prokaryotes (bacteria and archaea).

The theory holds that mitochondria, plastids such as chloroplasts, and possibly other organelles of eukaryotic cells represent formerly free-living prokaryotes taken one inside the other in endosymbiosis, around 1.5 billion years ago. In more detail, mitochondria appear to be related to Rickettsiales proteobacteria, and chloroplasts to nitrogen-fixing filamentous cyanobacteria.

Among the many lines of evidence supporting symbiogenesis are that new mitochondria and plastids are formed only through binary fission, and that cells cannot create new ones otherwise; that the transport proteins called porins are found in the outer membranes of mitochondria, chloroplasts and bacterial cell membranes; that cardiolipin is found only in the inner mitochondrial membrane and bacterial cell membranes; and that some mitochondria and plastids contain single circular DNA molecules similar to the DNA of bacteria.

History

Endosymbiotic theory

Kwang Jeon's experiment supports endosymbiosis. [I] Amoebae infected by x-bacteria [II] Many amoebae become sick and die [III] Survivors have x-bacteria living in their cytoplasm [IV] Antibiotics kill x-bacteria: host amoebae die as now dependent on x-bacteria.

The theory of symbiogenesis (Greek: σύν syn "together", βίωσις biosis "living", and γένεσις genesis "origin or birth") was first articulated by the Russian botanist Konstantin Mereschkowski in his work in 1910, The Theory of Two Plasms as the Basis of Symbiogenesis, a New Study or the Origins of Organisms, although the fundamentals of the idea already had appeared in his earlier 1905 work, The nature and origins of chromatophores in the plant kingdom.^[1][2][3] Mereschkowski was familiar with work by botanist Andreas Schimper, who had observed in 1883 that the division of chloroplasts in green plants closely resembled that of free-living cyanobacteria, and who had himself tentatively proposed (in a footnote) that green plants had arisen from a symbiotic union of two organisms.^[4] In 1918 the French scientist Paul Portier published Les Symbiotes in which he claimed that the mitochondria originated from a symbiosis process.^[5] Ivan Wallin extended the idea of an endosymbiotic origin to mitochondria in the 1920s.^[6][7] The Russian botanist Boris Kozo-Polyansky was the first to explain the theory in terms of Darwinian evolution.^[8] In his 1924 book Symbiogenesis: A New Principle of Evolution he wrote, "The theory of symbiogenesis is a theory of selection relying on the phenomenon of symbiosis."^[9] These theories were initially dismissed or ignored. More detailed electron microscopic comparisons between cyanobacteria and chloroplasts (for example studies by Hans Ris published in 1961^[10]), combined with the discovery that plastids and mitochondria contain their own DNA^[11] (which by that stage was recognized to be the hereditary material of organisms) led to a resurrection of the idea in the 1960s.

The theory was advanced and substantiated with microbiological evidence by Lynn Margulis in a 1967 paper, On the origin of mitosing cells.^[12] In her 1981 work Symbiosis in Cell Evolution she argued that eukaryotic cells originated as communities of interacting entities, including endosymbiotic spirochaetes that developed into eukaryotic flagella and cilia. This last idea has not received much acceptance, because flagella lack DNA and do not show ultrastructural similarities to bacteria or archaea (see also: Evolution of flagella and Prokaryotic cytoskeleton). According to Margulis and Dorion Sagan,^[13] "Life did not take over the globe by combat, but by networking" (i.e., by cooperation). The possibility that peroxisomes may have an endosymbiotic origin has also been considered, although they lack DNA. Christian de Duve proposed that they may have been the first endosymbionts, allowing cells to withstand growing amounts of free molecular oxygen in the Earth's atmosphere. However, it now appears that they may be formed de novo, contradicting the idea that they have a symbiotic origin.^[14]

It is thought that over millennia these endosymbionts transferred some of their own DNA to the host cell's nucleus (called "endosymbiotic gene transfer" or "endogenosymbiosis") during the evolutionary transition from a symbiotic community to an instituted eukaryotic cell. The endosymbiotic theory is considered to be a type of saltational evolution.^[15]

One model for the origin of mitochondria and plastids.

From endosymbionts to organelles

According to Keeling and Archibald,^[16] the usual way to distinguish organelles from endosymbionts is by their reduced genome sizes. As an endosymbiont evolves into an organelle, most of their genes are transferred to the host cell genome. The host cell and organelle need to develop a transport mechanism that enables transfer back of the protein products needed by the organelle but now manufactured by the cell. Cyanobacteria and α-proteobacteria are the most closely related free-living organisms to plastids and mitochondria respectively.^[17] Both cyanobacteria and α-proteobacteria maintain a large (>6Mb) genome encoding thousands of proteins.^[17] Plastids and mitochondria exhibit a dramatic reduction in genome size when compared to their bacterial relatives.^[17] Chloroplast genomes in photosynthetic organisms are normally 120-200kb^[18] encoding 20-200 proteins^[17] and mitochondrial genomes in humans are approximately 16kb and encode 37 genes, 13 of which are proteins.^[19] Using the example of the freshwater amoeboid, however, Paulinella chromatophora, which contains chromatophores found to be evolved from cyanobacteria, Keeling and Archibald argue that this is not the only possible criterion; another is that the host cell has assumed control of the regulation of the former endosymbiont's division, thereby synchronizing it with the cell's own division.^[16] Nowack and her colleagues^[20] performed gene sequencing on the chromatophore (1.02 Mb) and found that only 867 proteins were encoded by these photosynthetic cells. Comparisons with their closest free living cyanobacteria of the genus Synechococcus (having a genome size 3 Mb, with 3300 genes) revealed that chromatophores underwent a drastic genome shrinkage. Chromatophores contained genes that were accountable for photosynthesis but were deficient in genes that could carry out other biosynthetic functions; this observation suggests that these endosymbiotic cells are highly dependent on their hosts for their survival and growth mechanisms. Thus, these chromatophores were found to be non-functional for organelle-specific purposes when compared to mitochondria and plastids. This distinction could have promoted the early evolution of photosynthetic organelles.

The loss of genetic autonomy, that is, the loss of many genes from endosymbionts, occurred very early in evolutionary time.^[21] Taking into account the entire original endosymbiont genome, there are three main possible fates for genes over evolutionary time. The first fate involves the loss of functionally redundant genes,^[21] in which genes that are already represented in the nucleus are eventually lost.The second fate involves the transfer of genes to the nucleus.^{[17][21][22][23][24]} The loss of autonomy and integration of the endosymbiont with its host can be primarily attributed to nuclear gene transfer.^[24] As organelle genomes have been greatly reduced over evolutionary time, nuclear genes have expanded and become more complex.^[17] As a result, many plastid and mitochondrial processes are driven by nuclear encoded gene products.^[17] In addition, many nuclear genes originating from endosymbionts have acquired novel functions unrelated to their organelles.^[17][24]

The mechanisms of gene transfer are not fully known; however, multiple hypotheses exist to explain this phenomenon. The cDNA hypothesis involves the use of messenger RNA (mRNAs) to transport genes from organelles to the nucleus where they are converted to cDNA and incorporated into the genome.^[17][22] The cDNA hypothesis is based on studies of the genomes of flowering plants.^[17] Protein coding RNAs in mitochondria are spliced and edited using organelle-specific splice and editing sites.^[17] Nuclear copies of some mitochondrial genes, however, do not contain organelle-specific splice sites, suggesting a processed mRNA intermediate.^[17] The cDNA hypothesis has since been revised as edited mitochondrial cDNAs are unlikely to recombine with the nuclear genome and are more likely to recombine with their native mitochondrial genome. If the edited mitochondrial sequence recombines with the mitochondrial genome, mitochondrial splice sites would no longer exist in the mitochondrial genome.^[17] Any subsequent nuclear gene transfer would therefore also lack mitochondrial splice sites.^[17]

The bulk flow hypothesis is the alternative to the cDNA hypothesis, stating that escaped DNA, rather than mRNA, is the mechanism of gene transfer.^[17][22] According to this hypothesis, disturbances to organelles, including autophagy (normal cell destruction), gametogenesis (the formation of gametes), and cell stress, release DNA which is imported into the nucleus and incorporated into the nuclear DNA using non-homologous end joining (repair of double stranded breaks).^[22] For example, in the initial stages of endosymbiosis, due to a lack of major gene transfer, the host cell had little to no control over the endosymbiont.^[21] The endosymbiont underwent cell division independently of the host cell, resulting in many "copies" of the endosymbiont within the host cell.^[21] Some of the endosymbionts lysed (burst), and high levels of DNA were incorporated into the nucleus.^[21] A similar mechanism is thought to occur in tobacco plants, who show a high rate of gene transfer and whose cells contain multiple chloroplasts.^[21] In addition, the bulk flow hypothesis is also supported by the presence of non-random clusters of organelle genes, suggesting the simultaneous movement of multiple genes.^[22]

In 2015, the biologist Roberto Cazzolla Gatti provided evidence for a variant theory,^[25] endogenosymbiosis, in which not only are organelles endosymbiotic, but that pieces of genetic material from symbiotic parasites ("gene carriers" such as viruses, retroviruses and bacteriophages), are included in the host's nuclear DNA, changing the host's gene expression and contributing to the process of speciation.^[26]

Molecular and biochemical evidence suggests that mitochondria are related to Rickettsiales proteobacteria (in particular, the SAR11 clade,^[27][28] or close relatives), and that chloroplasts are related to nitrogen-fixing filamentous cyanobacteria.^[29][30]

Organellar genomes

Plastomes and mitogenomes

The human mitochondrial genome has retained genes encoding 2 rRNAs, 22 tRNAs, and 13 redox proteins.

The third and final possible fate of endosymbiont genes is that they remain in the organelles. Plastids and mitochondria, although they have lost much of their genomes, retain genes encoding rRNAs, tRNAs, proteins involved in redox reactions, and proteins required for transcription, translation, and replication.^[17][18][21] There are many hypotheses to explain why organelles retain a small portion of their genome; however no one hypothesis will apply to all organisms^[21] and the topic is still quite controversial.^[17] The hydrophobicity hypothesis states that highly hydrophobic (water hating) proteins (such as the membrane bound proteins involved in redox reactions) are not easily transported through the cytosol and therefore these proteins must be encoded in their respective organelles.^[17][21] The code disparity hypothesis states that the limit on transfer is due to differing genetic codes and RNA editing between the organelle and the nucleus.^[21] The redox control hypothesis states that genes encoding redox reaction proteins are retained in order to effectively couple the need for repair and the synthesis of these proteins.^[17][18][21] For example, if one of the photosystems is lost from the plastid, the intermediate electron carriers may lose or gain too many electrons, signalling the need for repair of a photosystem.^[18] The time delay involved in signalling the nucleus and transporting a cytosolic protein to the organelle results in the production of damaging reactive oxygen species.^[17][18][21] The final hypothesis states that the assembly of membrane proteins, particularly those involved in redox reactions, requires coordinated synthesis and assembly of subunits; however, translation and protein transport coordination is more difficult to control in the cytoplasm.^[21]

Non-photosynthetic plastid genomes

The majority of the genes in the mitochondria and plastids are related to the expression (transcription, translation and replication) of genes encoding proteins involved in either photosynthesis (in plastids) or cellular respiration (in mitochondria).^[17][18][21] One might predict, that the loss of photosynthesis or cellular respiration would allow for the complete loss of the plastid genome or the mitochondrial genome respectively.^[21] While there are numerous examples of mitochondrial descendants (mitosomes and hydrogenosomes) that have lost their entire organellar genome,^[31] non-photosynthetic plastids tend to retain a small genome.^[21] There are two main hypotheses to explain this occurrence:

The essential tRNA hypothesis notes that there have been no documented functional plastid-to-nucleus gene transfers of genes encoding RNA products (tRNAs and rRNAs).^[21] As a result, plastids must make their own functional RNAs or import nuclear counterparts.^[21] The genes encoding tRNA-Glu and tRNA-fmet, however, appear to be indispensable.^[21] The plastid is responsible for haem biosynthesis, which requires plastid encoded tRNA-Glu (from the gene trnE) as a precursor molecule.^[21] Like other genes encoding RNAs, trnE cannot be transferred to the nucleus.^[21] In addition, it is unlikely trnE could be replaced by a cytosolic tRNA-Glu as trnE is highly conserved; single base changes in trnE have resulted in the loss of haem synthesis.^[21] The gene for tRNA-formylmethionine (tRNA-fmet) is also encoded in the plastid genome and is required for translation initiation in both plastids and mitochondria.^[21] A plastid is required to continue expressing the gene for tRNA-fmet so long as the mitochondrion is translating proteins.^[21]

The limited window hypothesis offers a more general explanation for the retention of genes in non-photosynthetic plastids.^[32] According to the bulk flow hypothesis, genes are transferred to the nucleus following the disturbance of organelles.^[22] Disturbance was common in the early stages of endosymbiosis, however, once the host cell gained control of organelle division, eukaryotes could evolve to have only one plastid per cell.^[21] Having only one plastid severely limits gene transfer^[21] as the lysis of the single plastid would likely result in cell death.^[21][32] Consistent with this hypothesis,^[32] organisms with multiple plastids show an 80-fold increase in plastid-to-nucleus gene transfer compared to organisms with single plastids.^[32]

Evidence

There are many lines of evidence that mitochondria and plastids including chloroplasts arose from bacteria.^{[33][34][35][36][37]}

• New mitochondria and plastids are formed only through binary fission, the form of cell division used by bacteria and archaea.^[38]
• If a cell's mitochondria or chloroplasts are removed, the cell does not have the means to create new ones.^[39] For example, in some algae, such as Euglena, the plastids can be destroyed by certain chemicals or prolonged absence of light without otherwise affecting the cell. In such a case, the plastids will not regenerate.
• Transport proteins called porins are found in the outer membranes of mitochondria and chloroplasts and are also found in bacterial cell membranes.^[40][41][42]
• A membrane lipid cardiolipin is exclusively found in the inner mitochondrial membrane and bacterial cell membranes.^[43]
• Some mitochondria and some plastids contain single circular DNA molecules that are similar to the DNA of bacteria both in size and structure.^[44]
• Genome comparisons suggest a close relationship between mitochondria and Rickettsial bacteria.^[45]
• Genome comparisons suggest a close relationship between plastids and cyanobacteria.^[46]
• Many genes in the genomes of mitochondria and chloroplasts have been lost or transferred to the nucleus of the host cell. Consequently, the chromosomes of many eukaryotes contain genes that originated from the genomes of mitochondria and plastids.^[44]
• Mitochondrial and plastid ribosomes are more similar to those of bacteria (70S) than those of eukaryotes.^[47]
• Proteins created by mitochondria and chloroplasts use N-formylmethionine as the initiating amino acid, as do proteins created by bacteria but not proteins created by eukaryotic nuclear genes or archaea.^[48][49]

Comparison of chloroplasts and cyanobacteria showing their similarities.

Secondary endosymbiosis

Primary endosymbiosis involves the engulfment of a bacterium by another free living organism. Secondary endosymbiosis occurs when the product of primary endosymbiosis is itself engulfed and retained by another free living eukaryote. Secondary endosymbiosis has occurred several times and has given rise to extremely diverse groups of algae and other eukaryotes. Some organisms can take opportunistic advantage of a similar process, where they engulf an alga and use the products of its photosynthesis, but once the prey item dies (or is lost) the host returns to a free living state. Obligate secondary endosymbionts become dependent on their organelles and are unable to survive in their absence (for a review see McFadden 2001^[50]). RedToL, the Red Algal Tree of Life Initiative funded by the National Science Foundation highlights the role red algae or Rhodophyta played in the evolution of our planet through secondary endosymbiosis.

One possible secondary endosymbiosis in process has been observed by Okamoto & Inouye (2005). The heterotrophic protist Hatena behaves like a predator until it ingests a green alga, which loses its flagella and cytoskeleton, while Hatena, now a host, switches to photosynthetic nutrition, gains the ability to move towards light and loses its feeding apparatus.^[51]

The process of secondary endosymbiosis left its evolutionary signature within the unique topography of plastid membranes. Secondary plastids are surrounded by three (in euglenophytes and some dinoflagellates) or four membranes (in haptophytes, heterokonts, cryptophytes, and chlorarachniophytes). The two additional membranes are thought to correspond to the plasma membrane of the engulfed alga and the phagosomal membrane of the host cell. The endosymbiotic acquisition of a eukaryote cell is represented in the cryptophytes; where the remnant nucleus of the red algal symbiont (the nucleomorph) is present between the two inner and two outer plastid membranes.^{[citation needed]}

Despite the diversity of organisms containing plastids, the morphology, biochemistry, genomic organisation, and molecular phylogeny of plastid RNAs and proteins suggest a single origin of all extant plastids – although this theory is still debated.^[52][53]

Some species including Pediculus humanus (lice) have multiple chromosomes in the mitochondrion. This and the phylogenetics of the genes encoded within the mitochondrion suggest that mitochondria have multiple ancestors, that these were acquired by endosymbiosis on several occasions rather than just once, and that there have been extensive mergers and rearrangements of genes on the several original mitochondrial chromosomes.^[54]