RNA World

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RNA World
Weaker hypothesis There was a stage of evolution
at when RNA molecules performed both genetic and
catalytic roles. DNA later took over the genetic
role and proteins took over the catalytic
role. Stronger hypothesis The RNA world arose
de novo in the form of self replicating ribozymes.
Almost certainly true
The jury is still out
Lectures based on Joyce (2004) The antiquity of
RNA-based evolution Nature 418 214-221 Orgel
(2004) Prebiotic chemistry and the origin of the
RNA world. Crit. Rev. Biochem. Mol. Biol. 33
99-123 Jeffares, Poole Penny (1998) Relics from
the RNA world. J. Mol. Evol. 46 18-36.
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RNA world idea originated in 60s as a
theoretical solution to the chicken and egg
problem of DNA and proteins.
Self-splicing introns. First RNA catalysts to be
discovered. Tom Cech (1982). RNA World term
coined by Walter Gilbert (1986).
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Example of an RNA catalyst
Hammerhead ribozyme Cleaves RNA at a specific
point. Rolling circle mechanism of replication of
virus-like RNAs in plants. Chops long strand into
pieces.
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Chemistry required for RNA formation Prebiotic
synthesis of sugars - Formose reaction Butlerow
(1861) Formaldehyde ? Sugars (in aqueous
solution) 2 CH2O CH2OHCHO ? 2
CH2OHCHO formaldehyde glycoaldehyde
Glycoaldehyde catalyses its own formation
autocatalytic Glycoaldehyde reacts to form a
mixture of tetrose, pentose and hexose sugars.
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Oro (1950s) showed plausible prebiotic synthesis
of purines from HCN Many steps involved
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Other steps in prebiotic synthesis Pyrimidines
also ribose base ? nucleoside (weakest
link) phosphorylation of nucleosides ?
nucleotides
Conclusion from Orgel (2004) no convincing
prebiotic total synthesis of nucleotides many
individual steps have been demonstrated few
reactions give high yields complex mixtures
of products
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Clutter of RNA synthesis (Joyce) Why is this
particular set of monomers used for nucleic
acids? How is this set synthesized specifically?
Where is the chemistry occurring? Earth, or
space? Hydrothermal vents?
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Polymerization of nucleotides. Must be
activated - polymerization is uphill
thermodynamically.


?
In vivo synthesis of RNA works like this from
nucleoside triphosphates. This found to be too
slow in lab. Other activating groups were used.
Oligomers up to 16mers formed using Pb
catalyst. Up to 40mers formed using
Montmorillonite clay catalyst (Ferris) Dont know
how monomers were activated prebiotically.
Template directed synthesis of complementary
strand possible from many oligomers.
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An RNA organism must have had a
metabolism. Hypothetical pathway for RNA
catalyzed RNA synthesis (Joyce)
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Can we synthesize a replicase ribozyme? Johnston
et al. (2001) RNA-dependent RNA
polymerase. General should work on any
sequence In vitro selection from large pool of
random sequences Black ribozyme Red
template Orange primer Blue randomized
part In A, template is paired to ribozyme In C,
it is not. Blue domain recognizes non-specific
features of the template/primer.
Templates extended by up to 14 extra nucleotides.
Limited by ribozyme stability in solution.
Fidelity 96.7 (see error threshold theory)
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Are there alternatives to RNA?
RNA
a Threose Nucleic Acid TNA c
Glycerol derived nucleic acid b Peptide nucleic
acid PNA d Pyranosyl RNA
RNA hybridizes with other nucleic acids.
Information is not lost. DNA-RNA hybrids ? DNA
takes over at end of RNA world. Maybe TNA or PNA
preceded the RNA world. Information passed to
RNA. Would need to show that the alternative was
easier to synthesize than RNA.
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Two scenarios from Segré Lancet (2000) A RNA
first (strong RNA world hypothesis) B Lipids
first (lipid world hypothesis compositional
genomes metabolism without genes)
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When was the RNA world?
What preceded RNA? Another polymer? Metabolism
only?
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Why do we believe there was an RNA world (weaker
hypothesis) ? Translation depends on RNA mRNA
supplies the information for protein
synthesis. Active ingredient of the ribosome is
rRNA 3d structures show site of peptidyl
transferase reaction. Proteins probably added as
a late addition to the ribosome. tRNAs also
essential for translation.

• rRNA and tRNA must be relics of the RNA world.
• Which other RNAs might be relics? Jeffares (1998)
• catalytic RNA more likely to be ancient than
  information-carrying RNA (newly evolved metabolic
  functions would be proteins)
• ubiquitous (all domains of life prior to LUCA)
• central to metabolism

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Tendency RNA ? RNP (ribonulceoprotein) ?
protein In early RNP particles, proteins act as
cofactors to improve RNA catalysts. Eventually
proteins replace RNA in most functions. Need
genetic code to specify synthesis of long proteins
Probable relic RNAs Ribonuclease P RNaseP (is
a RNP) tRNA processing snoRNAs small
nucleolar RNAs rRNA processing (methylation of
bases in specific positions on rRNA) snRNAs
small nuclear RNAs mRNA processing in
eukaryotes - spliceosome U1, U2, U5
etc. several other possible candidates.
Estimated genome of the last riboorganism at
least 10-15 kbp probably double stranded RNA
genome (i.e. DNA came last, after RNA and
proteins). Possibly several copies each of small
linear chromosomes.