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Cited by 118Origins and Evolution of LifeRNA and protein synthesis mechanismsEvolution and Genetic Dynamics

Effect of Stalling after Mismatches on the Error Catastrophe in Nonenzymatic Nucleic Acid Replication

Open access
Rajamani, Sudha, Ichida, Justin K., Antal, Tibor, Treco, Douglas A., Leu, Kevin, Nowak, Martin A., Szostak, Jack W., Chen, Irene A.·2010·Journal of the American Chemical Society
DOI 10.1021/ja100780pPMC PMC2857888
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Abstract

The frequency of errors during genome replication limits the amount of functionally important information that can be passed on...

Integrity signals

Registry

Crossref · 10.1021/ja100780p

Cites

32 of 32 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

4 of 17 cited sources checked · 0 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    A different 3'-amine system studied by the Richert group had very fast reaction rates and nearly quantitative yield, suggesting that a 3'-amine system could be efficient enough to copy relatively long sequences.

    “In addition to the fairly efficient 3′-amine polymerization observed by Orgel and colleagues,(20) a different 3′-amine system has also been studied by the Richert group,(21) which exhibited very fast reaction rates with nearly quantitative yield, suggesting that a 3′-amine system has the potential to be efficient enough to copy relatively long sequences.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [21] source

      The Abstract (page not provided) reports rapid, essentially complete copying across a 15-nucleotide template, supporting the claim about speed, yield, and potential to copy longer sequences. But this is Mansy and colleagues’ system: it uses a 3′-amino-terminated primer with 2′-amino nucleotides, not a separate 3′-amine polymerization system studied by the Richert group. Richert-associated work appears only as reference 27 for the primer. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • Rests on an assumption: The 3'-amine system may resemble the biological 3'-5' linkage more closely than alternatives.
  • Premisecitation

    In the 3'-amino primer system, the rate of a single extension can be measured because the amine reacts much faster than a hydroxyl.

    “In this system, the rate of a single extension can be determined because the amine reacts much faster than a hydroxyl.3,13”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [3] source

      The Calculations passage describes converting RNA-virus mutation frequencies into mutation rates, and the Discussion concerns viral genome replication. Searches for a 3′-amino primer, single-extension kinetics, and amine-versus-hydroxyl reactivity found no passage addressing the claimed mechanism. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • cites [13] source
    • Rests on an assumption: The 3'-amine system may resemble the biological 3'-5' linkage more closely than alternatives.
  • Findingown data

    A nonenzymatic system exhibits stalling after mutations.

    “our results do demonstrate that a nonenzymatic system exhibits stalling after mutations”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The 3'-amine system may resemble the biological 3'-5' linkage more closely than alternatives.
  • Findingown data

    The absolute incorporation rate of G and C across their cognate bases was about 10 times greater than that of A and T.

    “The absolute rate of incorporation of G and C across their cognate bases was also ∼10 times greater than the rate of incorporation of A and T, consistent with trends from previous work(18) suggesting that hydrogen bonding may also contribute to the reaction rate.”
    Quote in the paperNot a substantial claim
  • Findingown data

    Misincorporations occurred mainly when copying A and T.

    “Misincorporations occurred predominantly when copying A and T”
    Quote in the paperNot a substantial claim
  • Classified as probably not a substantial claim. 15
  • May combine two claims. 11

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    The results differ somewhat from earlier fidelity estimates in a similar system, probably because of differences in ionic conditions and monomer concentrations.

    “Our results differ somewhat from previous estimates of fidelity in a similar system, probably because of differences in ionic conditions and monomer concentrations.(3)”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [3] source

      The Discussion (page unavailable) compares RNA-virus mutation-rate estimates, but does not attribute differences to ionic conditions or monomer concentrations. Searches for those conditions and for fidelity estimates in a similar system found no passage addressing the proposed explanation. (LLM, conf=0.75)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    Earlier work reports that nonenzymatic template-directed nucleic acid polymerization has error rates near 20%, corresponding to a genome of about five bases.

    “Previous work indicates that nonenzymatic, template-directed nucleic acid polymerization has high error rates (close to 20%), corresponding to a genome of roughly 5 bases,(3)”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [3] source

      The Abstract reports a mutation rate of roughly 0.2 per genome per replication for retroelements, not a 20% error rate for nonenzymatic polymerization. The Discussion concerns ribovirus mutation rates and small mutational target sizes; neither it nor the additional passages found for nonenzymatic polymerization and five-base genomes addresses the claimed relationship. (LLM, conf=0.76)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    Initial experiments showed that T incorporation was especially slow, causing relatively low fidelity when copying across template base A.

    “Initial experiments showed that the rate of incorporation of T was particularly slow, causing relatively low fidelity when copying across a template base A, so we increased the concentration of ImpdT to 40 mM in our reactions (compared with 10 mM for the other nucleotides).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The 3'-amine system may resemble the biological 3'-5' linkage more closely than alternatives.

  • May combine two claims.

    Findingown data

    Even without an enzyme, nonenzymatic polymerization showed substantial stalling: extension from any mismatch was slower than from its matched counterpart by a factor of 20-300, with Save = 124 ± 22.

    “Despite the lack of an enzyme, nonenzymatic polymerization showed substantial stalling, with the extension from any mismatch being slower than its matched counterpart by a factor of 20−300 (Save = 124 ± 22).”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: For the stalling-factor calculation, the genome is taken to have equal proportions of A, C, G, and T.

  • May combine two claims.

    Findingown data

    A mismatched terminus in the nascent sequence stalls extension and decreases the extension rate of a mutant sequence by more than two orders of magnitude.

    “The presence of a mismatched terminus in the nascent sequence stalls extension and effectively decreases the rate of extension of a mutant sequence by more than 2 orders of magnitude.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    When the genome is too long for a given mutation rate, full-length mutants outgrow the master sequence, and in a finite population the master sequence eventually disappears.

    “Thus, the mutants outgrow the master sequences because they all consume resources during replication, and in a finite population, the master sequence would eventually disappear.(8)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [8] source

  • May combine two claims.

    Interpretationreasoning

    Under the original Eigen model, a 7.6% mutation rate would be too high to sustain a functional genome at low fitness, with L* about 13.

    “According to the original Eigen model, a mutation rate of 7.6% would be too high to sustain a functional genome at low fitness (L* ≈ 13).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisereasoning

    Because L* depends only weakly logarithmically on r and prebiotic fitness is thought to have been small, the classical equation is often approximated as L* ≈ 1/μ, roughly one error per replication.

    “Because L* has a relatively weak logarithmic dependence on r and the prebiotic fitness is thought to have been relatively small, this equation is often approximated as L* ≈ 1/μ (corresponding to r = e) or roughly one error per replication.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    In Eigen's classical model, the master sequence survives only if the number of functionally informative sites L is below a critical value L* = (ln r)/μ.

    “In this classical model,(1) the master sequence can survive only if L is less than a critical L* = (ln r)/μ (Supporting Information).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1] source

  • May combine two claims.

    Interpretationreasoning

    A GC-rich genome would have a lower mutation rate; for an entirely GC genome, μ is about 0.8%.

    “so a GC-rich genome would have a lower mutation rate (e.g., for an entirely GC genome, μ ≈ 0.8%; see Methods and Materials for details of the calculation).”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    The maximum genome information is inversely proportional to the mutation rate.

    “In particular, the maximum genome information is inversely proportional to the mutation rate.(1)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1] source

  • May combine two claims.

    Premisecitation

    Earlier proposals for resolving Eigen's paradox either require special functions or have relatively limited magnitude.

    “However, these approaches either invoke special functions or are relatively limited in magnitude.6,7”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [6] source
    • cites [7] source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Although complementary strands were ignored in the simple model, the error threshold is similar for complementary replication.

    “In this simple model, the existence of complementary strands was ignored but the error threshold is similar for complementary replication.(9)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Mutation-rate data from RNA viruses, which seem to lie near the error threshold, support the inverse relation between maximum genome information and mutation rate.

    “Experimental data on mutation rates in RNA viruses, which appear to exist near this limit (the error threshold), also support this relationship.(2)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [2] source

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Enzymatic polymerization studies show that incorporation of an incorrect nucleotide causes primer extension to stall after the mutation, likely because the mismatched terminus has a suboptimal conformation.

    “However, studies of enzymatic polymerization show that if an incorrect nucleotide is incorporated then primer extension stalls after the mutation, presumably because of a suboptimal conformation at the mismatched terminus.(10)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] source

  • Classified as probably not a substantial claim.

    Premisereasoning

    Past the error threshold, the system undergoes a phase transition in which the master sequence disappears and genomes diffuse randomly through sequence space.

    “Beyond this point, the system undergoes a phase transition to a state in which the master sequence disappears and the genomes diffuse randomly through sequence space.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    One analysis of self-cleaving ribozymes found that 25% of bases could be mutated without destroying function, so physical genome length could exceed informative length by 25%.

    “For example, one analysis of self-cleaving ribozymes found that 25% of bases could be mutated without destroying function, so the physical length of the genome could exceed the informative length by 25%.(6)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [6] source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    The data may not represent mutations in the RNA world itself.

    “Our data may not be representative of mutations in the RNA world itself”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The 3'-amine system may resemble the biological 3'-5' linkage more closely than alternatives.

  • May combine two claims.

    Interpretationown data

    Because extension stalls after mismatches, accurate copies of a template tend to finish faster than mutant copies, so accurate copies can start a second replication round sooner.

    “As a result of postmismatch stalling, accurate copies of a template tend to be completed more rapidly than mutant copies and the accurate copies can therefore begin a second round of replication more quickly.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisenone given

    The classical model assumed that polymerization proceeds at the same speed whether or not an error occurs.

    “In the classical model, polymerization was assumed to proceed equally fast regardless of whether an error occurred.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Stalling after mismatched base pairs has been observed for several DNA polymerases, with matched-to-mismatched extension-rate ratios ranging from 10 to 10^6.

    “Stalling after base pairs are mismatched has been observed for several DNA polymerases, with the ratio of extension rates from a matched versus mismatched terminus (the stalling factor, S) ranging from 10 to 106.(11)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [11] source

  • Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

    Interpretationnone given

    These effects would eventually become obsolete as replication machinery became more accurate and cooperating networks emerged, but early on they could have helped start the evolution of functional genomes.

    “Eventually, these effects would become obsolete as the replication machinery evolved greater accuracy and cooperating networks emerged, but early on they could have served to “kick start” the evolution of functional genomes.”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: In the modified Eigen model, the master sequence has relative fitness r and replication resources are present at constant concentration.
    • The authors state this as an assumption: Strand separation happens often relative to the slow chemical replication process.
    • The authors state this as an assumption: The total density of the model system is conserved.
22 of 22

  • The authors state this as an assumption.

    For the stalling-factor calculation, the genome is taken to have equal proportions of A, C, G, and T.

    “In this article, we assume that the genome is equal parts A, C, G, and T for the purpose of the stalling factor calculation (FA = FC = FG = FT = 0.25).”

  • The authors state this as an assumption.

    In the modified Eigen model, the master sequence has relative fitness r and replication resources are present at constant concentration.

    “Following Eigen’s model, we assume that the relative fitness of the master sequence is r and resources for replication are available at constant concentration.”

  • The authors state this as an assumption.

    Strand separation happens often relative to the slow chemical replication process.

    “Strand separation is assumed to occur frequently compared with the relatively slow process of chemical replication (e.g., thermal cycling due to day−night changes or in convection cells (Supporting Information)).”

  • The authors state this as an assumption.

    The total density of the model system is conserved.

    “under the condition that the total density of the system is conserved ([X] + [Y] + [Z] = constant; see Supporting Information for a full description)”

  • The paper relies on this without support.

    Before this study, it was not known whether nonenzymatic polymerization slows after mutations.

    “However, it was previously unknown whether nonenzymatic polymerization would also slow after mutations.”

  • The paper relies on this without support.

    The 3'-amine system may resemble the biological 3'-5' linkage more closely than alternatives.

    “we chose to focus on a 3′-amine system because it may mimic the biological 3′−5′ linkage more closely.”
6 of 6

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Calculated overall error rates from that study were 5%-15%, which would severely limit the size of a primitive genome.

    “Calculated overall error rates from that study were 5%-15%, which would severely limit the size of a primitive genome.”

    From Protocells and RNA Self-Replication (2018) · cites this paper as Rajamani et al. 2010

    Results and Discussion, under “Mutation Rate of Nonenzymatic Polymerization” (page unavailable), calculates a 7.6 ± 1.4% average mutation rate for an equal-base genome, but does not report an overall range of 5%–15%. The Introduction explains that high error rates limit genome information in the classical model; the modified-error-threshold results say that stalling could nevertheless permit functional-length sequences. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • The error threshold is roughly proportional to the inverse of genome length.

    “The error threshold is roughly proportional to the inverse of genome length, which also raised the question of how genomes long enough to encode error correction could have evolved under high error rates (Eigen's paradox) [15], [27], [28].”

    From Thermodynamic Basis for the Emergence of Genomes during Prebiotic Evolution (2012) · cites this paper as [28]

  • Most errors in RNA-templated polymerization of imidazole-activated nucleotides result from G•U wobble pairing.

    “most errors result from G•U wobble pairing”

    From Protocells and RNA Self-Replication (2018) · cites this paper as Rajamani et al. 2010

    The Introduction and Results and Discussion describe experiments with DNA templates and deoxy-nucleotide monomers, not RNA-templated polymerization. The Mutation Rate section says misincorporations occurred predominantly when copying A and T, but does not identify G•U wobble pairing as their cause. The Choice of Experimental Model System section cautions that these data may not represent mutations in RNA. (LLM, conf=0.78)

    Experimental — accuracy not yet measured

  • Nonenzymatic RNA replication stalls substantially following introduction of a mismatch, leading to slower than expected rates of incorrect copy formation and thus an effectively greater copying accuracy.

    “nonenzymatic RNA replication has been shown to stall substantially following introduction of a mismatch, leading to slower than expected rates of incorrect copy formation and thus an effectively greater copying accuracy [117–119].”

    From The RNA world as a model system to study the origin of life (2015) · cites this paper as [118]

  • The phenomenon considered by Rajamani et al. is equivalent to some increasing of the fitness ratio.

    “Actually the considered phenomenon is equivalent to some increasing of the fitness ratio .”

    From Lethal mutants and truncated selection together solve a paradox of the origin of life (2011) · cites this paper as [51]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Stalling-factor formula cannot produce the reported average

    Minor

    The stated formula sums mismatch frequencies multiplied by stalling factors but does not divide by the total mismatch frequency. With an average mutation rate of 7.6% and every stalling factor at most 300, that formula cannot give more than 22.8, yet the reported average is 124.

  • Noninformative bases increase physical length by 33%, not 25%

    Minor

    If 25% of bases can be mutated without affecting function, the informative bases make up 75% of the physical length. The physical length therefore exceeds the informative length by 25/75, or about 33%, rather than 25%.

    Reported 25 · recomputed 33.333333

2 of 2

Cites

Flagged first, then by citations

Research works printed but not linked: 2

  1. Schuster, P.InThe Aptamer Handbook;Klussmann, S., Ed.Wiley-VCH:Weinheim, Germany, 2006; pp29−53.
  2. Chen L., 2005, Curr. Protoc. Nucleic Acid Chem., 13.14.11

Cited by

Sorted by citations

Related

Authors
Rajamani, S., Ichida, J. K., Antal, T., Treco, D. A., Leu, K., Nowak, M. A., Szostak, J. W., & Chen, I. A.
Affiliations
  • Howard Hughes Medical Institute (US)
  • FAS Center for Systems Biology and Program for Evolutionary Dynamics, Harvard University, Cambridge, Massachusetts 02138, and Howard Hughes Medical Institute, Department of Molecular Biology and the Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, Massachusetts 02114
Corresponding author
Chen, Irene A.
ORCID
Venue
Journal of the American Chemical Society
Publisher
American Chemical Society (ACS)
Published
2010-04-01
Volume
132
Issue
16
Pages
5880-5885
ISSN
  • 0002-7863 (ISSN-L)
  • 1520-5126
DOI
10.1021/ja100780p
PMC
PMC2857888
OpenAlex
W2073749448
Cited by
118
References
32
Citations by year
2026: 10 · 2025: 6 · 2024: 7 · 2023: 5 · 2022: 4 · 2021: 6 · 2020: 3 · 2019: 6 · 2018: 7 · 2017: 3 · 2016: 9 · 2015: 12 · 2014: 7 · 2013: 4 · 2012: 20
FWCI
5.88
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of the American Chemical Society (publishedVersion, other-oa)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • National Science Foundation (0434507)
  • Howard Hughes Medical Institute
  • Harvard University
  • National Institutes of Health (GM068763)
  • National Institute of General Medical Sciences (P50GM068763, GM-068763)
Topics
  • Physical Sciences › Physics and Astronomy › Astronomy and Astrophysics › Origins and Evolution of Life
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
Keywords
error catastrophe, template polymerization, origin of life, mutation rate
MeSH terms
Base Sequence, DNA, DNA Replication, Enzymes, Nucleic Acids, RNA, DNA Primers, Base Pair Mismatch, Dideoxynucleotides

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read under definition version 3 (extract-v3) on 2026-09-28.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-09-28.

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Statistics and arithmetic are recomputed, not judged.

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