The DOI matches its Crossref record; 74 of the 74 references it cites were found in a registry or an index; 3 of the 98 sources its claims cite were checked for support.
The modern molecular clock
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.
Overview
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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).
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Claims the paper makes
54 Not checked yet · 22 Own interpretation · 13 No basis given · 2 Supported so far · 2 Own method · 1 Supported
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In the paper
“In fact, the molecular clock is generally even sloppier: observations indicate that the pattern of substitution intervals for many genes has a broader distribution, which might be described as an 'overdispersed' Poisson distribution 11,13,14 .”
What the sources say
- Not checked yetcites [11] Gillespie, J. H. The Causes of Molecular Evolution (Oxford University Press, Oxford, UK, 1991).
- Not checked yetcites [13] Bickel, D. R. Implications of fluctuations in substitution rates: impact on the uncertainty of branch lengths and on relative-rate tests. J. Mol. Evol. 50, 381–390 (2000). source
- Supportedcites [14] Cutler, D. J. Estimating divergence times in the presence of an overdispersed molecular clock. Mol. Biol. Evol. 17, 1647–1660 (2000). source
The Introduction describes overdispersion as substitution counts with variance greater than the Poisson expectation and explains that a variable-rate Poisson process can produce the same broader distribution. In the empirical analysis (Performance Evaluation), the constant-rate Poisson model is rejected and one locus has an inferred index of dispersion nearly 20 times the Poisson expectation. The paper also models variation in the times between substitutions, consistent with the citing sentence’s description of substitution intervals. (LLM, conf=0.88)
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In the paper
“If many calibration dates are available - for example, if a series of samples from a single infected patient 62 or a collection of archived samples 63 is available - it becomes possible to test the constancy of rates across the viral phylogeny.”
What the sources say
- Not checked yetcites [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
- Supportedcites [63] Twiddy, S. S., Holmes, E. C. & Rambaut, A. Inferring the rate and time-scale of dengue virus evolution. Mol. Biol. Evol. 20, 122–129 (2003). source
The Introduction says the method uses sampling times from sequences isolated over a range of dates and directly tests the assumption of a single substitution rate. Materials and Methods describes the likelihood-ratio test comparing a single-rate dated-tip model with a model allowing different rates across branches. The supplied passages do not provide page numbers. (LLM, conf=0.92)
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In the paper
“First, the sloppy nature of the substitution rate results in large variance around the amount of genetic difference expected for any given time period, adding a large degree of imprecision to molecular date estimates 27 .”
What the sources say
- Supportedcites [27] Bromham, L., Rambaut, A., Fortey, R., Cooper, A. & Penny, D. Testing the Cambrian explosion hypothesis by using a molecular dating technique. Proc. Natl Acad. Sci. USA 95, 12386–12389 (1998). source
The Abstract says that variation in the rate of molecular evolution can affect date estimates and that the stochastic nature of the molecular clock precludes precise dating. The Results add that confidence intervals reflect stochastic error in the substitution process and are wide for molecular date estimates. These passages support the claim’s point about variation and imprecision. (LLM, conf=0.90)
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In the paper
“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 .”
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [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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In the paper
“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.”
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In the paper
“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 .”
What the sources say
- Not checked yetcites [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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In the paper
“However, there is, as yet, no evidence that environmental temperature influences the rate of molecular evolution 40,41 .”
What the sources say
- Not checked yetcites [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 yetcites [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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In the paper
“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).”
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In the paper
“In addition, the strength of selection on particular sites can change, producing bursts of substitutions as a molecule is adapted to a new role or responds to changes in another part of the genome.”
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In the paper
“But molecular dates for the origins of animal phyla 27 and orders of mammals and birds 68 are generally twice as old as the dates of origin indicated by the fossil record.”
What the sources say
- Not checked yetcites [27] Bromham, L., Rambaut, A., Fortey, R., Cooper, A. & Penny, D. Testing the Cambrian explosion hypothesis by using a molecular dating technique. Proc. Natl Acad. Sci. USA 95, 12386–12389 (1998). source
- Not checked yetcites [68] Madsen, O. et al.Parallel adaptive radiations in two major clades of placental mammals. Nature 409, 610–614 (2001). Used the quartet method which uses several calibration dates to allow for differences in substitution rate between lineages to support the hypothesis that modern mammals arose long before the final extinction of the dinosaurs. source
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In the paper
“The unexpected constancy of rate was explained by assuming that most changes to genes are effectively neutral.”
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In the paper
“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 .”
What the sources say
- Not checked yetcites [2] Korber, B. et al.Timing the ancestor of the HIV-1 pandemic strains. Science 288, 1789–1796 (2000). source
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In the paper
“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.”
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Probably not a substantial claim.
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In the paper
“Theory predicts several sources of variation in the rate of molecular evolution.”
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In the paper
“However, extrapolation has few constraints on the variances and biases, so uncertainty increases with the distance between the calibration point and the estimated node.”
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In the paper
“Selection of the substitution model governs the accuracy of genetic distance estimates and is therefore crucial to the accuracy of molecular dating.”
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In the paper
“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 .”
What the sources say
- Not checked yetcites [67] Page, R. D. M. & Holmes, E. C. Molecular Evolution: a Phylogenetic Approach (Blackwell Science, Oxford, UK, 1998).
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In the paper
“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.”
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In the paper
“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.”
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In the paper
“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.”
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“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.”
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In the paper
“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 .”
What the sources say
- Not checked yetcites [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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In the paper
“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 + .”
What the sources say
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In the paper
“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”
What the sources say
- Not checked yetcites [36] Martin, A. P. Metabolic rate and directional nucleotide substitution in animal mitochondrial DNA. Mol. Biol. Evol. 12, 1124–1131 (1995).
- Not checked yetcites [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
- Not checked yetcites [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
- Not checked yetcites [38] Bromham, L. Molecular clocks in reptiles: life history influences rate of molecular evolution. Mol. Biol. Evol. 19, 302–309. (2002). source
- Not checked yetcites [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
- Not checked yetcites [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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In the paper
“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.”
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In the paper
“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.”
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In the paper
“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 ).”
What the sources say
- Not checked yetcites [69] Conway Morris, S. Early metazoan evolution: reconciling paleontology and molecular biology. Am. Zool. 38, 867–877 (1998). source
- Not checked yetcites [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 yetcites [49] Bromham, L. Molecular clocks and explosive radiations. J. Mol. Evol. (in the press). source
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In the paper
“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 .”
What the sources say
- Not checked yetcites [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
- Not checked yetcites [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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In the paper
“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 .”
What the sources say
- Not checked yetcites [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 yetcites [71] Carroll, R. C. Towards a new evolutionary synthesis. Trends Ecol. Evol. 15, 27–32 (2000). source
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In the paper
“However, it could be related to population size effects if rapidly speciating lineages undergo frequent population subdivision 40 .”
What the sources say
- Not checked yetcites [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
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In the paper
“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”
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In the paper
“Mutation rate clearly varies between taxa 29 and much of this variation is due to differences in repair equipment (biochemical factors).”
What the sources say
- Not checked yetcites [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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In the paper
“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 .”
What the sources say
- Not checked yetcites [46] Barraclough, T. G. & Savolainen, V. Evolutionary rates and species diversity in flowering plants. Evolution 55, 677–683 (2001). source
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In the paper
“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.”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“There are three approaches to allowing for the variation in the rate of molecular evolution.”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
In the paper
“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 .”
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“A likelihood ratio test is used to compare the fit of a single substitution rate with a multiple-rate model.”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Mutations are divided into three categories: mutations for which selection is the predominant force (4N e σ s > 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 < 0.2).”
What the sources say
- Not checked yetcites [22] Ohta, T. & Kimura, M. On the constancy of the evolutionary rate of cistrons. J. Mol. Evol. 1, 18–25 (1971). source
- Not checked yetcites [23] Ohta, T. Very slightly deleterious mutations and the molecular clock. J. Mol. Evol. 26, 1–6 (1987). source
- Not checked yetcites [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
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
In the paper
“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 .”
What the sources say
- Not checked yetcites [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
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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) .”
What the sources say
- Not checked yetcites [22] Ohta, T. & Kimura, M. On the constancy of the evolutionary rate of cistrons. J. Mol. Evol. 1, 18–25 (1971). source
- Not checked yetcites [23] Ohta, T. Very slightly deleterious mutations and the molecular clock. J. Mol. Evol. 26, 1–6 (1987). source
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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.”
What the sources say
- Not checked yetcites [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
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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 .”
What the sources say
- Not checked yetcites [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 yetcites [2] Korber, B. et al.Timing the ancestor of the HIV-1 pandemic strains. Science 288, 1789–1796 (2000). source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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 .”
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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 .”
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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 .”
What the sources say
- Not checked yetcites [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.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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 .”
What the sources say
- Not checked yetcites [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 yetcites [49] Bromham, L. Molecular clocks and explosive radiations. J. Mol. Evol. (in the press). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“All molecular clock methods rely on accurate estimates of the genetic distance between sequences, and, in some cases, this measurement might be biased.”
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds. It may state two separate claims as one.
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.”
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?
In the citing paper
“Actually, single fossils may also bear their load of uncertainty in taxonomy identification and geological ages (11).”
From The timing of eukaryotic evolution: Does a relaxed molecular clock reconcile proteins and fossils? (2004) · cites this paper as [11]
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.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Box 4 | The nearly neutral theory: population size and the molecular clock · p. 6
“nearly neutral mutations, which are governed by both selection and drift (3 ≥ 4N e σ s ≤ 0.2)”
§ Box 4 | The nearly neutral theory: population size and the molecular clock · p. 6
“effectively neutral mutations, the fate of which is determined only by drift (4N e σ s < 0.2)”
Citations
Cites
Evolutionary trees from DNA sequences: A maximum likelihood approach.
Felsenstein, J. (1981) · Journal of Molecular Evolution · doi:10.1007/bf01734359 · Cited by 14,571
The Neutral Theory of Molecular Evolution
Kimura, M. (1979) · Scientific American · doi:10.1038/scientificamerican1179-98 · Cited by 7,687
The Neutral Theory of Molecular Evolution
Kimura, M. (1983) · Cambridge University Press eBooks · doi:10.1017/cbo9780511623486 · Cited by 6,300
On the Origin of Species by Means of Natural Selection
Livezey, R. L., & Darwin, C. R. (1953) · The American Midland Naturalist · doi:10.2307/2485224 · Cited by 5,431
A molecular timescale for vertebrate evolution
Kumar, S., & Hedges, S. B. (1998) · Nature · doi:10.1038/31927 · Cited by 1,936
Drake, J. W., Charlesworth, B., Charlesworth, D., & Crow, J. F. (1998) · Genetics · doi:10.1093/genetics/148.4.1667 · Cited by 1,932
King, J. L., & Jukes, T. H. (1969) · Science · doi:10.1126/science.164.3881.788 · Cited by 1,772
Body size, metabolic rate, generation time, and the molecular clock.
Martin, A. P., & Palumbi, S. R. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.9.4087 · Cited by 1,239 · cited 1×
“, then species with higher metabolic rates might generate higher concentrations of mutagens and incur more DNA damag”
BackgroundThe causes of molecular evolution
Gillespie, J. H. (1992) · Choice Reviews Online · doi:10.5860/choice.30-2064 · Cited by 1,214
A nonparametric approach to estimating divergence times in the absence of rate constancy.
Sanderson, M. J. (1997) · Molecular Biology and Evolution · doi:10.1093/oxfordjournals.molbev.a025731 · Cited by 1,156 · cited 1×
“A more promising approach is to explicitly model rate variation over the phylogen”
Background
Research works printed but not linked: 1
- Zuckerkandl, E. & Pauling, L. in Horizons in Biochemistry (eds Kasha, M. & Pullman, B.) 189–225 (Academic Press, New York, 1962).
Cited by
Sorted by citations
Relaxed Phylogenetics and Dating with Confidence
Drummond, A. J., Ho, S. Y. W., Phillips, M. J., & Rambaut, A. (2006) · PLoS Biology · doi:10.1371/journal.pbio.0040088 · Cited by 6,463
“Often paleontology or biogeography can provide a date for one or more points in a phylogeny, which are then used to “calibrate” the timescale for the rest of the phylogeny [3, 4 ].”
BackgroundOrthologs, Paralogs, and Evolutionary Genomics
Koonin, E. V. (2005) · Annual Review of Genetics · doi:10.1146/annurev.genet.39.073003.114725 · Cited by 1,323
Computational Molecular Evolution
Yang, Z. (2006) · doi:10.1093/acprof:oso/9780198567028.001.0001 · Cited by 1,152
Prevotella Diversity, Niches and Interactions with the Human Host
Tett, A., Pasolli, E., Masetti, G., Ercolini, D., & Segata, N. (2021) · Nature Reviews Microbiology · doi:10.1038/s41579-021-00559-y · Cited by 748
Reading the entrails of chickens: molecular timescales of evolution and the illusion of precision
Graur, D., & Martin, W. (2004) · Trends in Genetics · doi:10.1016/j.tig.2003.12.003 · Cited by 669
Metadata
- 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
- Published
- 2003-03
- Volume
- 4
- Issue
- 3
- Pages
- 216-224
- ISSN
- 1471-0056 (ISSN-L)
- 1471-0064
- 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
About these checks
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.
A language model drew the claims from the paper on 2026-10-06, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
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Statistics and arithmetic are recomputed, not judged.
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