The modern molecular clock

Key Points

  • Rates of molecular evolution can be remarkably constant over time, producing a molecular clock.

  • The constancy of rates was explained by the neutral theory by assuming that most changes to DNA or protein sequences are neutral — that is, driven by drift not selection.

  • The neutral theory has been refined to allow for the effect of population size on the chance of mutations of small selective effect being fixed in a population (the nearly neutral theory).

  • The molecular clock is a 'sloppy' clock: theory predicts that the rate of molecular evolution will be influenced by mutation rate, patterns of selection and population size.

  • Stochastic fluctuations in substitution rate over time in lineages (residual effects) make molecular date estimates imprecise.

  • Variation in rate between lineages can cause substantial bias in molecular date estimates.

  • Attempts to use molecular clocks to date evolutionary divergences must account for these sources of imprecision and bias, and variation in rates must be expressed in confidence intervals around date estimates.


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.

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Figure 1: Selectionist, neutral and nearly neutral theories.
Figure 2: A molecular clock for the Hawaiian islands.


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We thank A. Rambaut and A. Eyre-Walker for helpful comments.

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Correspondence to Lindell Bromham.

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The maximum-likelihood method takes a model of sequence evolution (essentially a set of parameters that describe the pattern of substitutions) and searches for the combination of parameter values that gives the greatest probability of obtaining the observed sequences.


A method that selects the tree that has the greatest posterior probability (the probability that the tree is correct), under a specific model of substitution.


A discrete frequency distribution of the number of independent events per time interval, for which the mean value is equal to the variance.


Evolution at, or above, the level of species; the patterns and processes of diversification and extinction of species over evolutionary time.


The process of evolution in populations: changing allele frequencies over generations, due to selection or drift.


A group of linked regulatory genes that are involved in patterning the animal body axis during development.


The reproductive strategy of an organism.


A 'cold-blooded' organism, such as a reptile, for which body temperature is dependent on the environment.


A 'warm-blooded' organism, such as a mammal or bird, for which body temperature is maintained independently of the environment.


(Ne). The equivalent number of breeding adults in a population after adjusting for complicating factors, such as reproductive dynamics. It is usually less that the actual number of living or reproducing individuals (the census population size N).


An increase in allele frequency to the point at which all individuals in a population are homozygous.


A life-history strategy in which only a subset of members of a group produce their own offspring, and others act as non-reproductive helpers, as in honeybees or naked molerats.


The random fluctuation that occurs in allele frequencies as genes are transmitted from one generation to the next. This is because allele frequencies in any sample of gametes that perpetuate the population might not represent those of the adults in the previous generation.


A measure of the variation around the central class of a distribution (the average squared deviation of the observations from their mean value).


A test for variation in the rate of molecular evolution between lineages, which compares the distance between each of a pair of taxa and an outgroup to determine the relative amount of change in each lineage since their last common ancestor.


A test for variation in the rate of molecular evolution between lineages, based on the expectation that under a uniform rate of substitution, the number of sites at which the amino-acid or nucleotide state is shared by the outgroup and only one of the two ingroups should be equal for both ingroups.


A method for hypothesis testing. The maximum of the likelihood that the data fit a full model of the data (in this case, multiple substitution rates) is compared with the maximum of the likelihood that the data fit a restricted model (a single substitution rate) and the likelihood ratio (LR) test statistic is computed. If the LR is significant, the full model provides a better fit to the data than does the restricted model.

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Bromham, L., Penny, D. The modern molecular clock . Nat Rev Genet 4, 216–224 (2003).

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