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Cited by 616Evolution and Genetic DynamicsGenomics and Phylogenetic StudiesEvolution and Paleontology Studies

The modern molecular clock

Bromham, Lindell, Penny, David·2003·Nature Reviews Genetics
DOI 10.1038/nrg1020
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Abstract

The discovery of the molecular clock--a relatively constant rate of molecular evolution--provided an insight into the mechanisms of molecular evolution, and created one of the most useful new tools in biology. The unexpected constancy of rate was explained by assuming that most changes to genes are effectively neutral. Theory predicts several sources of variation in the rate of molecular evolution. However, even an approximate clock allows time estimates of events in evolutionary history, which provides a method for testing a wide range of biological hypotheses ranging from the origins of the animal kingdom to the emergence of new viral epidemics.

AI snapshot

Written from the paper’s full text.

TL;DR

The molecular clock—a relatively constant rate of molecular evolution—was unexpected but is broadly explained by neutral and nearly neutral theory, and it provides a universal tool for dating evolutionary events. However, the clock is “sloppy” and rates vary among lineages, so molecular dates must be treated with appropriate confidence intervals and caution.

Key findings

  • Zuckerkandl and Pauling found a strikingly linear accumulation of amino-acid differences over evolutionary time, with each protein having a characteristic rate: histones were exceptionally slow, cytochrome c was faster but slower than haemoglobins, and fibrinopeptides were faster still; Kimura and Ohta explained this by suggesting most amino-acid changes are effectively neutral.
  • Rate variation arises through mutation rate, population size, and selective coefficients; examples include murid rodents evolving two to three times faster than hominid primates, and HIV evolving around a million times faster than mammalian genomes.
  • Molecular dates can conflict with fossil dates: molecular dates for the origins of animal phyla and orders of mammals and birds are generally twice as old as fossil dates, and published molecular dates for the rodent–primate split vary by as much as 100%.
  • A practical application: molecular clock dates place the last common ancestor of the main pandemic HIV strain in the 1930s, countering claims that the virus spread through contaminated polio vaccine in the 1950s.

Methods

  • Review article synthesizing the history, theory, and methods of molecular dating; no new primary data or analyses are presented.
  • Discusses calibration approaches (fossil record, biogeography, sample dates for viruses), substitution models, and clock tests (relative rates test, Tajima test, likelihood ratio test), plus maximum likelihood and Bayesian methods.
  • Uses examples from proteins, Hawaiian island birds and fruitflies, vertebrates, and viruses to illustrate rate constancy and variation.

Limitations

  • The paper states that the molecular clock is probabilistic and “sloppy,” with overdispersed substitution intervals adding large confidence intervals; lineage effects can systematically bias date estimates.
  • It notes operational errors: uncertain phylogenies, calibration-point errors, and biased genetic-distance estimates; clock tests lack power for shorter or slowly evolving sequences.
  • It states that few studies present confidence intervals that accurately portray clock variance, and that molecular dates are often point estimates; as a review, it does not resolve these issues with new data (evident from text).

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/nrg1020

Cites

74 of 74 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 98 cited sources checked · 0 supported · 0 flagged

  • Interpretationcitation
    § Box 1 | Measuring evolutionary time with a molecular clock · p. 2

    The variation in rate of molecular evolution between lineages warns against using a calibration rate calculated for one lineage to date another, often distantly related, lineage.

    “The variation in rate of molecular evolution between lineages warns against using a calibration rate calculated for one lineage to date another, often distantly related, lineage 1,28,48 .”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [1] Smith, A. B. & Peterson, K. J. Dating the time of origin of major clades: molecular clocks and the fossil record. Annu. Rev. Earth Planet. Sci. 30, 65–88 (2002). A review of the controversy surrounding dates for the Cambrian explosion of animal phyla and the early Tertiary radiation of modern mammals and birds. Written by a palaeontologist and a molecular geneticist, this review takes a critical look at the reliability of both fossil and molecular dates. source

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    • cites [28] Bromham, L. D., Rambaut, A., Hendy, M. D. & Penny, D. he power of relative rates tests depends on the data. J. Mol. Evol. 50, 296–301 (2000). source

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    • cites [48] Bromham, L. D., Phillips, M. J. & Penny, D. Growing up with dinosaurs: molecular dates and the mammalian radiation. Trends Ecol. Evol. 14, 113–118 (1999). source

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  • Premisenone given
    § Lindell Bromham* and David Penny ‡ · p. 1

    The amount of difference between the DNA of two species is a function of the time since their evolutionary separation.

    “The molecular clock arises from the observation that the amount of difference between the DNA of two species is a function of the time since their evolutionary separation.”
    Quote in the paperNot a substantial claim
  • Premisecitation
    § Box 1 | Measuring evolutionary time with a molecular clock · p. 2

    The choice of calibration date is crucial to the accuracy of molecular dates.

    “The choice of calibration date is crucial to the accuracy of molecular dates, as shown by the difference in date estimates from studies using the same data and methods but different calibration dates 48 .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [48] Bromham, L. D., Phillips, M. J. & Penny, D. Growing up with dinosaurs: molecular dates and the mammalian radiation. Trends Ecol. Evol. 14, 113–118 (1999). source

      Not checked in the free run.

  • Premisecitation
    § FIXATION · p. 5

    There is, as yet, no evidence that environmental temperature influences the rate of molecular evolution.

    “However, there is, as yet, no evidence that environmental temperature influences the rate of molecular evolution 40,41 .”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [40] Bromham, L. & Cardillo, M. Testing the link between the latitudinal gradient in species richness and rates of molecular evolution. J. Evol. Biol. 16, 200–207 (2003). source

      Not checked in the free run.

    • cites [41] Held, C. No evidence for slow-down of molecular substitution rates at subzero temperatures in Antarctic serolid isopods (Crustacea, Isopoda, Serolidae). Polar Biol. 24, 497–501 (2001). source

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  • Interpretationreasoning
    § Discovery of the molecular clock · p. 2

    The rate of accumulation of neutral mutations would be influenced only by the mutation rate, and so would be relatively constant, as long as the base mutation rate remained unchanged.

    “The rate of accumulation of these neutral mutations would be influenced only by the mutation rate, and so would be relatively constant, as long as the base mutation rate remained unchanged (BOX 3).”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim. 19
  • May combine two claims. 27

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given
    § Lindell Bromham* and David Penny ‡ · p. 1

    The unexpected constancy of rate was explained by assuming that most changes to genes are effectively neutral.

    “The unexpected constancy of rate was explained by assuming that most changes to genes are effectively neutral.”
    Quote in the paperNot a substantial claim

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

    Premisecitation
    § Lindell Bromham* and David Penny ‡ · p. 1

    Molecular clock dates place the last common ancestor of the main pandemic strain of HIV in the 1930s.

    “For example, molecular clock dates that place the last common ancestor of the main pandemic strain of human immunodeficiency virus (HIV) in the 1930s have been used to counter claims that the virus was spread through the distribution of contaminated polio vaccine in the 1950s (allegedly manufactured using tissue from chimpanzees infected with simian immunodeficiency virus) 2 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [2] Korber, B. et al.Timing the ancestor of the HIV-1 pandemic strains. Science 288, 1789–1796 (2000). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisenone given
    § Lindell Bromham* and David Penny ‡ · p. 1

    The molecular clock is a relatively constant rate of molecular evolution.

    “The discovery of the molecular clock - a relatively constant rate of molecular evolution provided an insight into the mechanisms of molecular evolution, and created one of the most useful new tools in biology.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given
    § Lindell Bromham* and David Penny ‡ · p. 1

    Theory predicts several sources of variation in the rate of molecular evolution.

    “Theory predicts several sources of variation in the rate of molecular evolution.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given
    § Box 1 | Measuring evolutionary time with a molecular clock · p. 2

    Extrapolation has few constraints on variances and biases, so uncertainty increases with the distance between the calibration point and the estimated node.

    “However, extrapolation has few constraints on the variances and biases, so uncertainty increases with the distance between the calibration point and the estimated node.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductreasoning
    § Box 1 | Measuring evolutionary time with a molecular clock · p. 2

    Selection of the substitution model governs the accuracy of genetic distance estimates and is crucial to the accuracy of molecular dating.

    “Selection of the substitution model governs the accuracy of genetic distance estimates and is therefore crucial to the accuracy of molecular dating.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductcitation
    § Box 1 | Measuring evolutionary time with a molecular clock · p. 2

    Counting differences between sequences fails to count multiple hits, so a model of sequence evolution is needed to estimate the true number of substitutions.

    “However, this approach will fail to count 'multiple hits' (repeated changes), so a model of sequence evolution is needed to estimate the true number of substitutions that have occurred, using the observed number 67 .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [67] Page, R. D. M. & Holmes, E. C. Molecular Evolution: a Phylogenetic Approach (Blackwell Science, Oxford, UK, 1998).

      Not checked in the free run.

  • May combine two claims.

    Study design and conductreasoning
    § Box 1 | Measuring evolutionary time with a molecular clock · p. 2

    The reliability of all molecular clock methods depends on the accuracy with which genetic distance is estimated, and on the appropriateness of the calibration rate.

    “The reliability of all molecular clock methods depends on the accuracy with which genetic distance is estimated, and on the appropriateness of the calibration rate.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning
    § Lindell Bromham* and David Penny ‡ · p. 1

    Even an approximate clock allows time estimates of events in evolutionary history, which provides a method for testing a wide range of biological hypotheses.

    “However, even an approximate clock allows time estimates of events in evolutionary history, which provides a method for testing a wide range of biological hypotheses ranging from the origins of the animal kingdom to the emergence of new viral epidemics.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisereasoning
    § FIXATION · p. 5

    Mitochondrial DNA is copied by DNA polymerase γ, which has a higher error rate than other mammalian DNA polymerases, and this contributes to the higher mutation rate of mitochondrial genes over nuclear genes.

    “Even within mammalian cells, different replication and repair enzymes vary in mutation rate: mitochondrial DNA is copied by DNA polymeraseγ , which has a higher error rate than other mammalian DNA polymerases,and this contributes to the higher mutation rate of mitochondrial genes over nuclear genes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning
    § Box 2 | Controversial clocks for explosive radiations · p. 4

    Small populations are more severely affected by stochastic fluctuations in allele frequencies, so genetic drift can overpower selection for alleles with small selection coefficients.

    “Small populations are more severely affected by stochastic fluctuations in allele frequencies, so genetic drift (random sampling error on allele frequencies) can overpower selection for alleles with small selection coefficients.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § The molecular clock is a 'sloppy' clock · p. 3

    The amount of divergence between genes tends to increase with the time since evolutionary separation, and in many cases the increase seems linear.

    “This constancy of rates is broadly supported by observation: the amount of divergence between genes tends to increase with the time since evolutionary separation, and in many cases the increase seems linear, as in the classic example of globin genes 3 .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [3] Zuckerkandl, E. & Pauling, L. in Horizons in Biochemistry (eds Kasha, M. & Pullman, B.) 189–225 (Academic Press, New York, 1962).

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    Premisecitation
    § Box 3 | The neutral theory and the molecular clock · p. 5

    According to the neutral theory, the overall mutation rate is the sum of deleterious, neutral, and positive mutations.

    “According to the neutral theory of Kimura 4,72 (FIG. 1b) , the overall mutation rate ( µ ) is the sum of deleterious ( µ -), neutral ( µ º), and positive ( µ + ) mutations, µ = µ - +µ º +µ + .”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [4] Kimura, M. & Ohta, T. On the rate of molecular evolution. J. Mol. Evol. 1, 1–17 (1971). source

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    • cites [72] Kimura, M. The Neutral Theory of Molecular Evolution (Cambridge University Press, Cambridge, UK, 1983). source

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    Premisecitation
    § FIXATION · p. 5

    Ectotherms have lower substitution rates than endotherms, smaller-bodied species of vertebrates with faster metabolic rates have higher substitution rates than larger-bodied species, and animal mitochondria have a higher rate of molecular evolution than nuclear rates.

    “This is consistent with the observations that ECTOTHERMS have lower substitution rates than ENDOTHERMS 36 , that smaller-bodied species of vertebrates with faster metabolic rates have higher substitution rates than larger-bodied species 35,37-39 and that animal mitochondria, which are at the site of oxidative phosporylation, have a higher rate of molecular evolution than nuclear rates 34 (it would”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [36] Martin, A. P. Metabolic rate and directional nucleotide substitution in animal mitochondrial DNA. Mol. Biol. Evol. 12, 1124–1131 (1995).

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    • cites [35] Martin, A. P. & Palumbi, S. R. Body size, metabolic rate, generation time and the molecular clock. Proc. Natl Acad. Sci. USA 90, 4087–4091 (1993). Showed a relationship between body size and the rate of molecular evolution for vertebrates using estimates of absolute substitution rates. This paper showed that the life history of a species must influence the rate of molecular evolution. source

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    • cites [37] Bromham, L., Rambaut, A. & Harvey, P. H. Determinants of rate variation in mammalian DNA sequence evolution. J. Mol. Evol. 43, 610–621 (1996). source

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    • cites [38] Bromham, L. Molecular clocks in reptiles: life history influences rate of molecular evolution. Mol. Biol. Evol. 19, 302–309. (2002). source

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    • cites [39] Mooers, A. Ø. & Harvey, P. H. Metabolic rate, generation time and the rate of molecular evolution in birds. Mol. Phylogenet. Evol. 3, 344–350 (1994). source

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    • cites [34] Rand, D. M. Thermal habit, metabolic rate and the evolution of mitochondrial DNA. Trends Ecol. Evol. 9, 125–131 (1994). source

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  • May combine two claims.

    Premisecitation
    § Discovery of the molecular clock · p. 2

    A given protein has a characteristic rate of evolution, but genes differ in their characteristic rates.

    “An early and unexpected finding from the molecular revolution was the discovery that a given protein has a characteristic rate of evolution, but that genes differ in their characteristic rates.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisereasoning
    § How reliable is the molecular clock? · p. 6

    Because of the universality of DNA (or RNA), molecular clocks can reach all timescales of evolution, from population divergences to the last common ancestor of the five kingdoms of life.

    “Because of the universality of DNA (or RNA), molecular clocks can reach all timescales of evolution, from population divergences to the last common ancestor of the five kingdoms of life.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing). May combine two claims.

    Premisecitation
    § Box 2 | Controversial clocks for explosive radiations · p. 3

    Many palaeontologists suggest that the discrepancy between molecular and palaeontological dates shows that molecular clocks can be systematically inaccurate, because some process associated with explosive radiations could speed the molecular clock.

    “Conversely, many palaeontologists suggest that the discrepancy between molecular and palaeontological dates shows that molecular clocks can be systematically inaccurate, because some process associated with explosive radiations could speed the molecular clock 69,70 (although no supporting evidence has yet been found for this hypothesis 49 ).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [69] Conway Morris, S. Early metazoan evolution: reconciling paleontology and molecular biology. Am. Zool. 38, 867–877 (1998). source

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    • cites [70] Valentine, J., Jablonski, D. & Erwin, D. Fossils, molecules and embryos: new perspectives on the Cambrian explosion. Development 126, 851–859 (1999). source

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    • cites [49] Bromham, L. Molecular clocks and explosive radiations. J. Mol. Evol. (in the press). source

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    Premisecitation
    § FIXATION · p. 5

    Murid rodents have less efficient excision-repair mechanisms than humans, and this is consistent with the higher rate of molecular evolution in murid rodents than in hominids.

    “For example, murid rodents (rats, mice and hamsters) have less efficient excisionrepair mechanisms than humans 31 and this is consistent with the higher rate of molecular evolution in murid rodents than in hominids 32 .”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [31] Hart, R. W. & Setlow, R. B. Correlation between deoxyribonucleic acid excision-repair and life-span in a number of mammal species. Proc. Natl Acad. Sci. USA 71, 2169–2173 (1974). source

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    • cites [32] Li, W. -H., Ellesworth, D. L., Krushkal, J., Chang, B. H. -J. & Hewett-Emmett, D. Rates of nucleotide substitution in primates and rodents and the generation-time effect hypothesis. Mol. Phylogenet. Evol. 5, 182–187 (1996). source

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  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing). May combine two claims.

    Premisecitation
    § Box 2 | Controversial clocks for explosive radiations · p. 3

    Some researchers suggest that the pace and degree of change in explosive radiations is too great to be explained by Darwinian microevolutionary processes, and that special mechanisms must be invoked.

    “Some researchers suggest that the pace and degree of change in explosive radiations is too great to be explained by Darwinian MICROEVOLUTIONARY processes, and that special mechanisms must be invoked,such as rapid change by developmental macromutations involving the HOX GENE COMPLEX 70,71 .”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [70] Valentine, J., Jablonski, D. & Erwin, D. Fossils, molecules and embryos: new perspectives on the Cambrian explosion. Development 126, 851–859 (1999). source

      Not checked in the free run.

    • cites [71] Carroll, R. C. Towards a new evolutionary synthesis. Trends Ecol. Evol. 15, 27–32 (2000). source

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    Interpretationcitation
    § GENETIC DRIFT · p. 6

    The faster rate of molecular evolution in more rapidly diversifying lineages could be related to population size effects if rapidly speciating lineages undergo frequent population subdivision.

    “However, it could be related to population size effects if rapidly speciating lineages undergo frequent population subdivision 40 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [40] Bromham, L. & Cardillo, M. Testing the link between the latitudinal gradient in species richness and rates of molecular evolution. J. Evol. Biol. 16, 200–207 (2003). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given
    § How reliable is the molecular clock? · p. 6

    If the rate of molecular evolution is relatively constant, then the amount of genetic difference between two species gives a measure of the time since their evolutionary separation.

    “if the rate of molecular evolution is relatively constant, then the amount of genetic difference between two species gives a measure of the time since their evolutionary separation”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § Different rates for different groups · p. 4

    Mutation rate clearly varies between taxa and much of this variation is due to differences in repair equipment.

    “Mutation rate clearly varies between taxa 29 and much of this variation is due to differences in repair equipment (biochemical factors).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [29] Drake, J., Charlesworth, B., Charlesworth, D. & Crow, J. Rates of spontaneous mutation. Genetics 148, 1667–1686 (1998). Observable mutation rates, when measured per genome per generation, are remarkably similar across widely divergent organisms, indicating that natural selection might shape optimum mutation rates. source

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    Interpretationcitation
    § GENETIC DRIFT · p. 6

    It is possible that the population size effect could account for the association between the diversification rate of flowering plant lineages and rates of molecular evolution.

    “It is possible that the population size effect could also account for the intriguing association between the diversification rate of flowering plant lineages (speciation minus extinction) and rates of molecular evolution 46 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [46] Barraclough, T. G. & Savolainen, V. Evolutionary rates and species diversity in flowering plants. Evolution 55, 677–683 (2001). source

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    Interpretationreasoning
    § Box 4 | The nearly neutral theory: population size and the molecular clock · p. 6

    The nearly neutral theory describes how the rate of molecular evolution can vary not only with changes in the mutation rate, but also through the changing balance between selection and drift.

    “So, the nearly neutral theory describes how the rate of molecular evolution can vary not only with changes in the mutation rate, but also through the changing balance between selection and drift.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given
    § Dating with confidence · p. 8

    There are three approaches to allowing for the variation in the rate of molecular evolution.

    “There are three approaches to allowing for the variation in the rate of molecular evolution.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § Estimating dates when rates vary · p. 7

    Clock tests lack power for shorter sequences (or genes with low rates of change) and will detect only a relatively low proportion of cases of rate variation for the types of sequence typically used in molecular clock studies.

    “However, these clock tests lack power for shorter sequences (or genes with low rates of change) and will detect only a relatively low proportion of cases of rate variation for the types of sequence that are typically used in molecular clock studies 28 .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [28] Bromham, L. D., Rambaut, A., Hendy, M. D. & Penny, D. he power of relative rates tests depends on the data. J. Mol. Evol. 50, 296–301 (2000). source

      Not checked in the free run.

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

    Premisenone given
    § Molecular clocks for emerging diseases · p. 8

    A likelihood ratio test is used to compare the fit of a single substitution rate with a multiple-rate model.

    “A likelihood ratio test is used to compare the fit of a single substitution rate with a multiple-rate model.”
    Quote in the paperNot a substantial claim

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

    Premisecitation
    § Box 4 | The nearly neutral theory: population size and the molecular clock · p. 6

    Mutations are divided into three categories: selection predominant (4N_e σ_s > 3); nearly neutral (3 ≥ 4N_e σ_s ≤ 0.2); and effectively neutral (4N_e σ_s < 0.2).

    “Mutations are divided into three categories: mutations for which selection is the predominant force (4N e σ s &gt; 3); nearly neutral mutations, which are governed by both selection and drift (3 ≥ 4N e σ s ≤ 0.2); and effectively neutral mutations, the fate of which is determined only by drift (4N e σ s &lt; 0.2).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [22] Ohta, T. & Kimura, M. On the constancy of the evolutionary rate of cistrons. J. Mol. Evol. 1, 18–25 (1971). source

      Not checked in the free run.

    • cites [23] Ohta, T. Very slightly deleterious mutations and the molecular clock. J. Mol. Evol. 26, 1–6 (1987). source

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    • cites [24] Ohta, T. Near-neutrality in evolution of genes and gene regulation. Proc. Natl Acad. Sci. USA 99, 16134–16137 (2002). The most recent exposition of the nearly-neutral model, in which the effects of weak selection depend both on the selection coefficient of the mutation and the size of the population in which the mutant occurs. source

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  • May combine two claims.

    Premisecitation
    § How reliable is the molecular clock? · p. 6

    The nearly neutral theory predicts that the rate of molecular evolution is influenced by mutation rate, population size and the relative proportions of sites with different selective coefficients; these factors might differ between genes, between species and over time, potentially resulting in consistent bias in date estimates.

    “Second, the nearly neutral theory predicts that the rate of molecular evolution is influenced by mutation rate, population size and the relative proportions of sites with different selective coefficients; these factors might differ between genes, between species and over time, potentially resulting in consistent bias in date estimates 28 .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [28] Bromham, L. D., Rambaut, A., Hendy, M. D. & Penny, D. he power of relative rates tests depends on the data. J. Mol. Evol. 50, 296–301 (2000). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Box 4 | The nearly neutral theory: population size and the molecular clock · p. 6

    Slightly deleterious mutations tend to be removed by selection in very large populations, but can be fixed by chance in smaller populations where selection is overpowered by random sampling events (genetic drift).

    “Slightly deleterious mutations will tend to be removed by selection in very large populations; however, they can be fixed by chance in smaller populations in which selection can be overpowered by random sampling events (GENETIC DRIFT) .”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [22] Ohta, T. & Kimura, M. On the constancy of the evolutionary rate of cistrons. J. Mol. Evol. 1, 18–25 (1971). source

      Not checked in the free run.

    • cites [23] Ohta, T. Very slightly deleterious mutations and the molecular clock. J. Mol. Evol. 26, 1–6 (1987). source

      Not checked in the free run.

    • cites [24] Ohta, T. Near-neutrality in evolution of genes and gene regulation. Proc. Natl Acad. Sci. USA 99, 16134–16137 (2002). The most recent exposition of the nearly-neutral model, in which the effects of weak selection depend both on the selection coefficient of the mutation and the size of the population in which the mutant occurs. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Box 4 | The nearly neutral theory: population size and the molecular clock · p. 7

    Molecular dates for Hemignathus and Drosophila confirm the order of colonization and produce a remarkably linear relationship between genetic divergence and time when DNA distance is plotted against island age.

    “Molecular dates for Hemignathus (panel b ) and Drosophila (panel c ) confirm this order of colonization, and produce a remarkably linear relationship between genetic divergence and time when DNA distance is plotted against island age.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] Fleischer, R. C., McIntosh, C. E. & Tarr, C. L. Evolution on a volcanic conveyor belt: using phylogeographic reconstructions and K-Ar based ages of the Hawaiian islands to estimate molecular evolutionary rates. Mol. Ecol. 7, 533–545 (1998). source

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    Premisenone given
    § Estimating dates when rates vary · p. 8

    Molecular evolutionary theory has led to the prediction that species can differ in their rate of molecular evolution through changes to traits that influence mutation rate, population size or selective coefficients, but the measurable effect of these predicted influences has only recently begun to be investigated for a wide range of taxa.

    “Molecular evolutionary theory has led to the prediction that species can differ in their rate of molecular evolution through changes to traits that influence mutation rate, population size or selective coefficients, but the measurable effect of these predicted influences has only recently begun to be investigated for a wide range of taxa.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § Molecular clocks for emerging diseases · p. 8

    Several dates can be used to fit a linear relationship between genetic distance and time, which might subsequently be used to estimate the rate of molecular evolution or the time of origin of the last common ancestor of all included samples.

    “Several dates can be used to fit a linear relationship between genetic distance and time, which might subsequently be used to estimate the rate of molecular evolution 62 or the time of origin of the last common ancestor of all included samples 2 .”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [62] Shankarappa, R. et al. Consistent viral evolutionary changes associated with the progression of human immunodeficiency virus type 1 infection. J. Virol. 73, 10489–10502 (1999). source

      Not checked in the free run.

    • cites [2] Korber, B. et al.Timing the ancestor of the HIV-1 pandemic strains. Science 288, 1789–1796 (2000). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Estimating dates when rates vary · p. 7

    Estimating maximum and minimum possible rates for a given data set requires several calibration dates, which are not always available, and gives conservative assessments of molecular dates suitable only for rejecting particular hypotheses as inconsistent with the data.

    “Estimating maximum and minimum possible rates for a given data set requires several calibration dates, which are not always available, and gives conservative assessments of molecular dates that are suitable only for rejecting particular hypotheses as being inconsistent with the data 55 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [55] Bromham, L. D. & Hendy, M. D. Can fast early rates reconcile molecular dates to the Cambrian explosion? Proc. R. Soc. Lond. B 267, 1041–1047 (2000). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning
    § Box 4 | The nearly neutral theory: population size and the molecular clock · p. 7

    The high variance from residual effects makes date estimates imprecise, but lineage effects might bias date estimates, so estimates based on a constant rate might produce consistently over- or under-estimated dates.

    “The high variance that arises from residual effects makes date estimates imprecise, but lineage effects, in which different species have different characteristic rates, might bias date estimates - that is, estimates based on the assumption of a constant rate might produce consistently over- or under-estimated dates.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § Estimating dates when rates vary · p. 7

    Failure to detect rate variation can cause systematic error in date estimates, because undetected rate variation can lead to consistently overestimated dates of divergence.

    “Failure to detect rate variation can cause systematic error in date estimates, because undetected rate variation can lead to consistently overestimated dates of divergence 28 .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [28] Bromham, L. D., Rambaut, A., Hendy, M. D. & Penny, D. he power of relative rates tests depends on the data. J. Mol. Evol. 50, 296–301 (2000). source

      Not checked in the free run.

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

    Premisecitation
    § Molecular clocks for emerging diseases · p. 8

    Similar methods have been developed that use Bayesian statistics to select the most likely parameters of molecular evolution for a set of viral sequences, including substitution rates and timing of ancestral nodes.

    “Similar methods have been developed that use Bayesian statistics to select the most likely parameters of molecular evolution for a set of viral sequences, including the substitution rates and timing of ancestral nodes 64 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [64] Drummond, A., Pybus, O. G. & Rambaut, A. Inference of viral evolutionary rates from molecular sequences. Adv. Parasitol. (in the press). A review of the methods used to estimate substitution rates in viruses, including estimating molecular dates when rates vary.

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning
    § Estimating dates when rates vary · p. 7

    The Bayesian method relies on the validity of many assumptions, some of which might be inappropriate for the data being tested, such as the assumption that a constant rate of lineage origination and extinction, counter to the proposed 'explosion'.

    “However, the method relies on the validity of many assumptions, some of which might be inappropriate for the data being tested (such as the assumption that a constant rate of lineage origination and extinction, counter to the proposed 'explosion') (BOX 2).”
    Quote in the paperSubstantial claim

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

    Premisecitation
    § Box 4 | The nearly neutral theory: population size and the molecular clock · p. 7

    Compounding residual and lineage errors are operational errors in measuring the rate of molecular evolution, which include uncertainty in the relationships between taxa, errors in calibration points and uncertainties in the mechanism of evolution.

    “Compounding these residual and lineage errors in the clock are operational errors in measuring the rate of molecular evolution, which include uncertainty in the relationships between taxa (the evolutionary tree), errors in calibration points and uncertainties in the mechanism of evolution 1,49 .”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [1] Smith, A. B. & Peterson, K. J. Dating the time of origin of major clades: molecular clocks and the fossil record. Annu. Rev. Earth Planet. Sci. 30, 65–88 (2002). A review of the controversy surrounding dates for the Cambrian explosion of animal phyla and the early Tertiary radiation of modern mammals and birds. Written by a palaeontologist and a molecular geneticist, this review takes a critical look at the reliability of both fossil and molecular dates. source

      Not checked in the free run.

    • cites [49] Bromham, L. Molecular clocks and explosive radiations. J. Mol. Evol. (in the press). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given
    § Box 4 | The nearly neutral theory: population size and the molecular clock · p. 7

    All molecular clock methods rely on accurate estimates of the genetic distance between sequences, and in some cases this measurement might be biased.

    “All molecular clock methods rely on accurate estimates of the genetic distance between sequences, and, in some cases, this measurement might be biased.”
    Quote in the paperNot a substantial claim
40 of 40

  • The paper relies on this without support.

    Molecular dates are frequently presented as point estimates, or with sample errors that represent the difference between estimates in the same study.

    “Part of the difficulty of assessing the reliability of molecular clocks is that molecular dates are frequently presented as point estimates, or with sample errors that represent the difference between estimates in the same study.”

  • The paper relies on this without support.

    Few studies present molecular date estimates with confidence intervals that accurately portray the variance in the clock due to the sloppiness of the tick rate, or the lineage variation in rates.

    “Few studies present molecular date estimates with confidence intervals that accurately portray the variance in the clock due to the sloppiness of the tick rate, or the lineage variation in rates.”
2 of 2

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?

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.

  • Nearly neutral and effectively neutral categories overlap

    Minor

    The stated inequality for nearly neutral mutations includes values below 0.2, which the next category also classifies as effectively neutral. The categories therefore overlap rather than defining separate ranges.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Zuckerkandl, E. & Pauling, L. in Horizons in Biochemistry (eds Kasha, M. & Pullman, B.) 189–225 (Academic Press, New York, 1962).

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Related

Authors
Bromham, L., & Penny, D.
Affiliations
  • University of Sussex (GB)
  • Allan Wilson Centre (NZ)
Corresponding author
Bromham, Lindell
ORCID
Bromham, Lindell
Venue
Nature Reviews Genetics
Publisher
Springer Science and Business Media LLC
Published
2003-03
Volume
4
Issue
3
Pages
216-224
ISSN
  • 1471-0056 (ISSN-L)
  • 1471-0064
DOI
10.1038/nrg1020
OpenAlex
W2062220010
Semantic Scholar
07e298aa4bc7299c0bfd8164d900b90ce80102a2
Cited by
615
References
74
Citations by year
2026: 9 · 2025: 15 · 2024: 17 · 2023: 14 · 2022: 11 · 2021: 25 · 2020: 21 · 2019: 21 · 2018: 17 · 2017: 20 · 2016: 27 · 2015: 24 · 2014: 50 · 2013: 40 · 2012: 27
FWCI
3.24
Type
journal article
Language
en
Open access
closed
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Reviews Genetics (publishedVersion)
  • PubMed (publishedVersion)
  • Figshare (submittedVersion)
  • ANU Open Research (Australian National University) (submittedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Phylogenetic Studies
  • Physical Sciences › Earth and Planetary Sciences › Paleontology › Evolution and Paleontology Studies
Keywords
molecular clock, molecular evolution rate, neutral theory of molecular evolution, rate variation, divergence time estimation, evolutionary history, viral epidemics
MeSH terms
Animals, Disease Outbreaks, DNA, Genetics, Population, Humans, Models, Genetic, Mutation, Population Density, Proteins, Selection, Genetic, Time Factors, Evolution, Molecular, Communicable Diseases, Emerging, History, Ancient

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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.

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