The modern molecular clock

In the paper

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

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

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.”

In the paper

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

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.”

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.”

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).

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.”

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.”

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.”

In the paper

“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.”

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).

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

• Not checked yetcites [4] Kimura, M. & Ohta, T. On the rate of molecular evolution. J. Mol. Evol. 1, 1–17 (1971). source
• Not checked yetcites [72] Kimura, M. The Neutral Theory of Molecular Evolution (Cambridge University Press, Cambridge, UK, 1983). source

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

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.”

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.”

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

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

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

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

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”

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

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

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.”

In the paper

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

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

In the paper

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

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

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

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

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

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.”

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

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

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.”

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

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.

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).”

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

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.”