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On the origin of the genetic code Eörs Szathmáry
Eötvös University, Dept
of Plant Systematics,
Ecology and Theoretical
Biology
Centre for the
Conceptual Foundations
of Science, Munich
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To the memory of Sergei Rodin
• Evolutionary scientist named to Susumu
Ohno Chair in Theoretical Biology
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A major transition
• Novel way of using genetic information
• Division of labour between nucleic acids and proteins (replication, storage AND catalyis): molecular „germ” and „soma”
• Replicability and enzymatic function disturb each other
• Origin likely to comprise some idiosyncratic steps
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Unambiguous and degenerate
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The structure of the genetic code
• Amino acids in
the same
column of the
genetic code
are more
related to each
other physico-
chemically
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Central nucleotide and amino acid
properties
Carl Woese
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Constraints on codon reshuffling
for statistical investigations
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Significance of some patterns
„The genetic
code is one in
a million” for
polarity
(Freeland and
Hurst)
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Amino acid biosynthesis in E. coli
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Biosynthetic relationships
Tzei-Fei Wong
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Biosynthesis and amino acid chemistry
BOTH have shaped the code
• The code within the codons (Taylor &
Coates, 1989): first letter correlates with
biosynthesis, second letter with chemisty
• Szathmáry, E. & Zintzaras, E. (1992) A
statistical test of hypotheses on the
organization and origin of the genetic
code. J. Mol. Evol. 35, 185-189.
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The RNA world may have preceded
the RNA-protein world
• Easy optimisation (with limits)
• Many artifical ribozymes (BUT no replicase)
• Coenzymes
• Ribozyme doing peptidyl transfer during protein
synthesis in ribosomes
• Amino acyl-tRNA synthetases are NOT the most
ancient proteins
• 20 residues are better than 4 in catalysis
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Possibility for an experimental test
of the role of RNA stereochemistry
• Szathmáry, E. (1990) Towards the evolution of ribozymes. Nature 344, 115.
• Generate aptamers against different amino acids: see whether there is specific binding at all
• Search for codonic or anticodonic sequence accumulation in the binding sites
• Draw conclusions
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Important ribozyme activities for the
emergence of translation
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The fascinating work of Michael
Yarus
• Consistently carrying out
the research programme
for amino acid binding
aptamers
• Looking for increasingly
statistically significant
results
• Trying to put it into the
context of evolution
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The minimal GCCU/GUGGC
ribozyme system
• The smallest ribozyme that
carries out a complex group
transfer is the sequence
GUGGC-3’,
• Acting to aminoacylate GCCU-
3’ (and host a manifold of
further reactions) in the
presence of substrate PheAMP.
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Tryptophan-binding aptamers
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The smallest typtophan binder
• The anticodon is CCA
• 13 fully conserved
nucleotides (26 bits of
information)
• Selective among
hydrophobic changes
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The force of aptamer selection
(Yarus)
• Using recent sequences for 337 independent
binding sites directed to 8 amino acids and
containing 18,551 nucleotides in all, we show a
highly robust connection between amino acids and
cognate coding triplets within their RNA binding
sites.
• The apparent probability (P) that cognate triplets
around these sites are unrelated to binding sites is
congruent with 5.3 x 10(-45) for codons overall,
and P congruent with 2.1 x 10(-46) for cognate
anticodons.
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Yarus aptamer codon/anticodon
table (2009)
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Forces may have changed in strength
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But what was the initial advantage?
• Evolution has no foresight
• Should confer some immediate advantage
• Concept of exaptation (preadaptation)
• Coded protein enzymes as culmination of a protracted phase of evolution
• Origin of the genetic code and protein synthesis are not necessariy the same thing
• Evolution is opportunistic
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My reservation against uncoded
translation and statistical proteins
• Very wasteful process, initial selective advantage is unclear relative to the high cost of the machinery
• It is like proposing a scenario for the origin of language with long sentences but no meaning, where even word-meaning pairs are statistical!
• They usually completely ignore Yarus’s results!
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Replicability and enzyme action are
in conflict
An independent catalytic alphabet is a cool
idea—provided you can get to it
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Coding coenzyme handle (CCH)
hypothesis for the origin of the genetic
code (1990, 1993,…)
• This mechanism
works only if binding
between the kissing
hairpins follows the
umambiguous, but
degenerate principle of
the current genetic
code
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Piecemeal vocabulary extension
• Amino acids are added and utilised one by
one
• No vicious error feedback as far as amino
acids are not involved (at the beginning) in
the functioning of synthetase ribozymes
• Coding precedes translation
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Why indirect binding through base-
pairing? • N number of amino acids
• M number of metabolic enzymes
• If metabolic ribozymes specifically and directly bind amino acid cofactors, then 2 * M functionalities
• THE SITE FOR AMINO ACID BINDING WOULD BLOCK THE AA’S SPECIFIC GROUPS NO GOOD FOR CATALYSIS
• In contrast, only M specific synthetases are needed IF AMINO ACIDS ARE CHARGED TO SPECIFIC HANDLES!
• If M >> N, then choose synthetases
• Bind cofactors by their handles through base pairing (cheap)
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Cofactor use by aptamers
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CCH generates a prediction
• Missed previously
• Footprints of the evolution for catalytic
potential should be found in codon
clustering
• Kun et al. (2008) In: M. Barbieri (eds)
Codes of Life. Springer, Berlin.
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Amino acid catalytic propensities
• Joint work with Kun, Pongor and Jordán (2008)
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Significance of some patterns
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Catalytic propensity and properties
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Highest catalytic and β-turn
propensities
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Substitution connectivity based on
the BLOSUM matrix
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A minimalist enzyme
• Chorismate
mutase built
of 9 amino
acids only
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Chiral histidine selection by D-
ribose RNA (Yarus) • The invariant choice of L-amino acids and D-ribose RNA for biological
translation requires explanation.
• Chiral choice using mixed, equimolar D-ribose RNAs having 15, 18,
21, 27, 35, and 45 contiguous randomized nucleotides was analyzed.
• These are used for simultaneous affinity selection of the smallest bound
and eluted RNAs using equal amounts of L- and D-His immobilized on
an achiral glass support, with racemic histidine elution.
• The most prevalent/smallest RNA sites are reproducibly and repeatedly
selected and there is a four- to sixfold greater abundance of L-histidine
sites. RNA’s chiral D-ribose therefore yields a more frequent fit to L-
histidine.
• Thus, if D-ribose RNA were first chosen biologically, translational L-
His usage could have followed.
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Transfer RNAs with complementary anticodons:
Could they reflect early evolution of
discriminative genetic code adaptors? (1993)
• With regard to the anticodon loop and stem of pairs of
consensus tRNAs, complementary distances were
considerably less than direct distances-i.e., antiparallel
pairing invariably yielded fewer mismatches than direct
pairing.
• Each pair of pre-tRNAs with complementary anticodons
should have been almost identical with each other except for
their three central bases.
• The above situation appears to have dictated the early
establishment of direct links between anticodons and the
type of amino acids with which tRNAs are to be charged.
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The presence of codon-anticodon
pairs in the acceptor stem of
tRNAs (1996)
• In pairs of consensus tRNAs with complementary
anticodons, their bases at the 2nd position of the
acceptor stem were also complementary.
• Accordingly, inverse complementarity was also
evident at the 71st position of the acceptor stem.
• The parallelism is especially impressive for the
pairs of tRNAs recognized by aminoacyl-tRNA
synthetases (aaRS) from the opposite classes.
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Two types of aminoacyl-tRNA synthetases
could be originally encoded by
complementary strands of the same nucleic
acid (1995)
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The growth of the
adaptor molecule
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The first possible tetrad
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ALL members of the first tetrad are
metabolically important
GLY
GCC
ALA
GGC
GUC
ASP
GAC
VAL
CU GA
• RNA synthesis (Gly,
Asp)
• Coenzyma A synthesis
(Val, Asp, Ala)
• Asp is also
catalytically important
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Complementary anticodons and
parallel expansion into the catalytic
and structural worlds
• As a rule, pairs of complementary triplets encode
the functionally very different amino acids, most
often those with a high catalytic propensity (His,
Asp, Glu, Lys, Arg) contrasted with those with a
low catalytic but high structural (beta sheet
building) propensity (Val, Ile, Leu, Phe, Ala)
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Second tetrad, catalytic expansion,
and the formation of the anticodon
loop?
ARG
GCG
ALA
CGC
GUG
HIS
CAC
VAL
CU GA
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Experimentation with catalytic mini
RNAs (Yarus, 2010)
• The small ribozyme initially trans-phenylalanylates a partially complementary 4-nt RNA selectively at its terminal 2’-ribose hydroxyl using PheAMP.
• The initial 2’ Phe-RNA product can be elaborated into multiple peptidyl-RNAs.
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Protein buildup on RNA scaffolds
• Shrinking RNA cores
• Selection for peptidyl-transferase activity
• Initially, proteins were strongly associated
with RNAs
• Could not fold by themselves
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Proteins from pieces (Lupas,
2003)
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Lupas’ conclusion
• The peptides forming these building blocks would
not in themselves have had the ability to fold, but
would have emerged as cofactors supporting RNA-
based replication and catalysis (the 'RNA world').
• Their association into larger structures and
eventual fusion into polypeptide chains would have
allowed them to become independent of their RNA
scaffold, leading to the evolution of a novel type of
macromolecule: the folded protein.
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Ribosomal proteins cannot fold by
themselves (Lupas)
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Thanks for your attention!
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An ancient genetic code at the
anticodon?
• In eubacteria, a paralog of glutamyl-tRNA
synthetase, which lacks the tRNA-binding
domain, was found to aminoacylate tRNAAsp not
on the 30-hydroxyl group of the acceptor stem but
on a cyclopentene diol of the modified nucleoside
queuosine present at the wobble position of
anticodon loop.
• This modified nucleoside might be a relic of an
ancient code.
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Amino acids in tRNA modifications
• At positions 34 and 37 of tRNA
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Modified queuosine