The modern molecular clock

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

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.”

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

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

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).”

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.”

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

In the paper

“Therefore, the fixation of nearly-neutral alleles of small selective effect is expected to be greatest in small populations 23,24 .”

What the sources say

• 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

In the paper

“This is a fundamental result; it predicts that the long-term rate of neutral molecular evolution in species is the same as the neutral mutation rate in individuals.”

In the paper

“They reported a strikingly linear rate of accumulation of amino-acid differences over evolutionary time.”

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).

In the paper

“In this way, population fluctuations might add to the sloppiness of the molecular clock.”

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
• Not checked yetcites [14] Cutler, D. J. Estimating divergence times in the presence of an overdispersed molecular clock. Mol. Biol. Evol. 17, 1647–1660 (2000). source

In the paper

“The neutral theory allows for two sources of rate variation in the molecular clock: the 'sloppiness' of the 'tick rate' and changes in the mutation rate.”

In the paper

“The nearly neutral theory also predicts that any consistent effect on effective population size could influence substitution rate (BOX 4).”

In the paper

“In a more recent example, the nucleotide distance between sister species on Hawaiian islands, plotted against geological estimates of island age, gave impressively linear relationships for both birds and fruitflies 10 (FIG. 2).”

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

In the paper

“But, in addition to imprecision arising from the variability in the substitution process, the tick rate of the clock can also vary consistently between different species, such that some branches of the phylogeny have a faster rate of molecular evolution than others.”

In the paper

“The predicted correlation of generation time with mutation rate 24 has been supported by studies that compare the rates of molecular evolution with generation time (or its correlate, body size) across a range of genes for several vertebrate species 35,37-39 .”

What the sources say

• 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
• 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

In the paper

“Dickerson 5 compared what was then known about the protein structures of histones, cytochrome c , haemoglobins and fibrinopeptides, and concluded that their different rates of change could be explained by the proportion of neutral sites that each protein contained - the greater the proportion of neutral sites, the faster the rate of molecular evolution.”

What the sources say

• Not checked yetcites [5] Dickerson, R. E. The structure of cytochrome c and rates of molecular evolution. J. Mol. Evol. 1, 26–45 (1971). source

In the paper

“Given the lack of a relationship between phenotypic evolution and molecular rates 19-21 , it seems unlikely that the observed faster rate of molecular evolution in more rapidly diversifying lineages is a result of species adapting to new niches.”

What the sources say

• Not checked yetcites [19] Papadopoulos, D. et al. Genomic evolution during a 10,000-generation experiment with bacteria. Proc. Natl Acad. Sci. USA 96, 3807–3812 (1999). A laboratory experiment comparing rates of morphological and molecular evolution in bacterial populations. Although adaptive phenotypic evolution was fastest at the beginning, DNA substitutions accumulated steadily through the experiment, indicating that the molecular clock is decoupled from the pace of adaptive evolution. source
• Not checked yetcites [20] Bromham, L., Woolfit, M., Lee, M. S. Y. & Rambaut, A. Testing the relationship between morphological and molecular rates of change along phylogenies. Evolution 56, 1921–1930 (2002). source
• Not checked yetcites [21] Wyles, J. S., Kunkel, J. G. & Wilson, A. C. Birds, behavior, and anatomical evolution. Proc. Natl Acad. Sci. USA 80, 4394–4397 (1983). source

In the paper

“Laboratory experiments on bacteria show that a 'mutator' allele, which raises the mutation rate, can be indirectly selected for because it increases the chance of an advantageous mutation arising 33 .”

What the sources say

• Not checked yetcites [33] Chao, L. & Cox, E. C. Competition between high and low mutating strains ofEscherichia coli. Evolution 37, 125–134 (1983). source

In the paper

“If most amino-acid changes are neutral, or deleterious, then the predicted constant rate of protein change produces a molecular clock.”

In the paper

“According to this model, the rate of gene evolution is governed by the overall mutation rate and the proportion of sites at which changes are neutral 6 (FIG. 1b).”

What the sources say

• Not checked yetcites [6] Penny, D., McComish, B. J., Charleston, M. A. & Hendy, M. D. Mathematical elegance with biochemical realism: the covarion model of molecular evolution. J. Mol. Evol. 53, 711–723 (2001). source

In the paper

“Pseudogenes, and other sequences with no effect on fitness, have a fast rate of molecular evolution because most changes to the sequence are allowed.”

In the paper

“However, empirical studies have also shown a great deal of variation in the rate of molecular evolution.”

In the paper

“The neutral theory predicts that, for a given mutation rate and proportion of neutral sites, the rate of molecular evolution should be constant.”

In the paper

“In this case, molecular date estimates could be systematically inaccurate 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

In the paper

“So, according to a neutral model, population size cancels out to leave the molecular evolution rate determined by the mutation rate ( µ º).”

In the paper

“Although it is possible that the overall rate of adaptation or morphological change of a species might influence the molecular clock, so far there has been little evidence to support this proposition from either experimental studies 19 or comparative analyses 20,21 .”

What the sources say

• Not checked yetcites [19] Papadopoulos, D. et al. Genomic evolution during a 10,000-generation experiment with bacteria. Proc. Natl Acad. Sci. USA 96, 3807–3812 (1999). A laboratory experiment comparing rates of morphological and molecular evolution in bacterial populations. Although adaptive phenotypic evolution was fastest at the beginning, DNA substitutions accumulated steadily through the experiment, indicating that the molecular clock is decoupled from the pace of adaptive evolution. source
• Not checked yetcites [20] Bromham, L., Woolfit, M., Lee, M. S. Y. & Rambaut, A. Testing the relationship between morphological and molecular rates of change along phylogenies. Evolution 56, 1921–1930 (2002). source
• Not checked yetcites [21] Wyles, J. S., Kunkel, J. G. & Wilson, A. C. Birds, behavior, and anatomical evolution. Proc. Natl Acad. Sci. USA 80, 4394–4397 (1983). source

In the paper

“Although it is broadly true that the longer two species are separated, the more protein or DNA differences will accumulate between them, the nearly neutral theory of molecular evolution (BOX 4) leads us to expect that the rate of molecular evolution can vary in three ways: through changes to mutation rate, population size or selective coefficients.”

In the paper

“So, if a population undergoes a marked reduction in population size due to an environmental catastrophe, this event might be accompanied by a burst of fixation of nearly-neutral alleles.”

In the paper

“The three-dimensional structure assumed by proteins has an important effect on the patterns of substitutions, as modelled by a structurally constrained neutral model 15 : although many sequences can fold to the same three-dimensional structure, different sequences have different numbers of 'neighbours' that they can mutate to and still maintain thermodynamic stability.”

What the sources say

• Not checked yetcites [15] Bastolla, U., Porto, M., Roman, H. E. & Vendruscolo, M. Lack of self-averaging in neutral evolution of proteins. Phys. Rev. Lett. 89, article no. 208101 (2002). This original paper follows the evolution of protein sequences that are restricted in their predicted tertiary structure. It shows, using basic biochemical principles, that the variability in rates of a molecular clock is expected to be higher than for a simple Poisson process. source

In the paper

“Motoo Kimura and Tomoko Ohta 4 explained the constant characteristic rate for each protein by suggesting that most amino-acid changes in a protein were effectively neutral - that is, changing the amino-acid sequence had no influence on the fitness of an organism and,therefore, the rate of change was not affected by natural selection.”

What the sources say

• Not checked yetcites [4] Kimura, M. & Ohta, T. On the rate of molecular evolution. J. Mol. Evol. 1, 1–17 (1971). source

In the paper

“This distribution of intervals between substitution events ('ticks') - commonly described by a POISSON DISTRIBUTION 12 - adds large confidence intervals to date estimates because the time taken to produce the observed substitutions cannot be known precisely.”

What the sources say

• Not checked yetcites [12] Zheng, Q. On the dispersion index of a Markovian molecular clock. Math. Biosci. 172, 115–128 (2001). This gives a statistical view of the expected variability in rates that occur when the simple probabilistic models of molecular evolution are allowed to increase in complexity. source

In the paper

“For example, the substitution rate in murid rodents is, on average, two to three times faster than the rate in hominid primates (apes and humans) 32 .”

What the sources say

• 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

In the paper

“However, both theory and observation show that the molecular clock is much more complex than was initially supposed.”

In the paper

“In the case of endogenous retroviruses (embedded in the genome of their host), dates of origin can be estimated without a calibration date by comparing the two long terminal repeats (LTRs) that flank the viral genome - a method that has helped uncover the history of viral DNA in the human genome 60,61 .”

What the sources say

• Not checked yetcites [60] Bromham, L. The human zoo: endogenous retroviruses in the human genome. Trends Ecol. Evol. 17, 91–97 (2002). source
• Not checked yetcites [61] Tristem, M. Identification and characterization of novel human endogenous retrovirus families by phylogenetic screening of the Human Genome Mapping Project database. J. Virol. 74, 3715–3730 (2000). source

In the paper

“Several rate-variable molecular clock methods have been developed and applied to viral sequences with serial sample dates - for example, using maximum likelihood to optimize the substitution rate over a phylogeny of sequences with known isolation dates to estimate the unknown internal nodes 66 .”

What the sources say

• Not checked yetcites [66] Rambaut, A. Estimating the rate of molecular evolution: incorporating non-contemporaneous sequences into maximum likelihood phylogenies. Bioinformatics 16, 395–399 (2000). source

In the paper

“But for other viruses, complex processes of molecular evolution, such as recombination and selection, cast doubt on the information value of genetic distances as a measure of time 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

In the paper

“This difference is probably due to a combination of factors, including differences in DNA-repair mechanisms, generation time, metabolic rate and effective population size.”

In the paper

“Tomoko Ohta 22-24 provided an important extension of the neutral theory by recognizing the crucial role of effective population size in the influence of selection.”

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

In the paper

“Viral molecular clocks also show how the degree of clock like sequence evolution varies between different taxa or genes.”

In the paper

“For some viruses - such as Dengue fever 63 or influenza 65 - observable constancy of rates provides a convincing molecular clock.”

What the sources say

• Not checked yetcites [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
• Not checked yetcites [65] Fitch, W. M., Leiter, J. M., Li, X. Q. & Palese, P. Positive Darwinian evolution in human influenza A viruses. Proc. Natl Acad. Sci. USA 88, 4270–4274 (1991). source

In the paper

“For example, published molecular dates for the split between rodents and primates vary by as much as 100% (REF. 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

In the paper

“If the genetic distance between rodents and primates is used to estimate their date of divergence by assuming a constant rate of molecular evolution, this rate difference can result in molecular dates that are consistently too old 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

In the paper

“So, a mutation would be effectively neutral if |s| < 1/4N e , where N e is the effective population size.”

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

In the paper

“Such confidence intervals allow molecular dates to be used to test evolutionary hypotheses within the bounds of the accuracy and precision of molecular clocks, by asking whether the range of possible date estimates is consistent with a specific evolutionary hypotheses 26 (for example, that the animal phyla arose in the early Cambrian 27 ) (BOX 2).”

What the sources say

• Not checked yetcites [26] Rambaut, A. & Bromham, L. Estimating divergence dates from molecular sequences. Mol. Biol. Evol. 15, 442–448 (1998). source
• 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

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
• Not checked yetcites [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

In the paper

“We cannot expect a universal linear relationship between distance and time because of the many factors that can influence the rate of molecular evolution.”

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

• 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

In the paper

“In some cases, molecular dates produced by different methods contradict each other 1,48,49 .”

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

In the paper

“In addition, modelling too many parameters can lead to a loss of power to distinguish between variants of a model 59 .”

What the sources say

• Not checked yetcites [59] Rannala, B. Identifiability of parameters in MCMC Bayesian inference of phylogeny. Syst. Biol. 51, 754–760 (2002). source

In the paper

“Some seem to contradict other lines of evidence, such as the study that produced a molecular date estimate for the split between kingdoms that is markedly younger than the earliest fossils 47 .”

What the sources say

• Not checked yetcites [47] Doolittle, R. F., Feng, D. F., Tsang, S., Cho, G. & Little, E. Determining divergence times of the major kingdoms of living organisms with a protein clock. Science 271, 470–477 (1996). source

In the paper

“Viral molecular clocks are most commonly calibrated using past samples, such as sequences from stored tissue samples 2,63 .”

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
• Not checked yetcites [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

In the paper

“Problems with the accuracy and precision of molecular clocks can be demonstrated by comparing studies that use different genes, calibrations or methods, and produce different date estimates for the same divergence 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