The Modern Molecular Clock

REVIEWS

THE MODERN MOLECULAR CLOCK
Lindell Bromham* and David Penny ‡
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.
The molecular revolution has influenced all areas of biology.The human genome project has markedly reduced the time it takes to identify candidate disease genes, molecular markers are now a standard tool in conservation biology and agricultural techniques from pest control to improving crop yields depend on molecular methods. Although it is less in the public eye than these frontline applications, molecular data has also revolutionized the study ofevolutionary biology. One way in which DNA evidence is transforming evolutionary biology is by providing a ‘molecular clock’ to put a new timescale on the history of life. 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. This provides a universal tool not only for placing pastevolutionary events in time (BOX 1), but also for exploring the mechanisms and processes of evolution. The evolutionary dates measured by molecular clocks have been controversial, particularly if they clash with estimates taken from more traditional sources such as the fossil record1. This conflict has been most evident in the debate over the timing of several important evolutionary events. One is theorigin of the main types (phyla) of animal, which appear as an ‘explosion’ of fossil forms in the early Cambrian. Another is the replacement of dinosaurs by modern birds and mammals, traditionally placed in the early Tertiary following evidence of an extraterrestrial impact 65 million years ago (Mya) (BOX 2). Resolving the timing of these events has clear implications for our understanding of thetempo and mode of important transitions in evolution. But the controversy over the molecular clock is not just the concern of evolutionary theorists: the practical benefits of the molecular clock are immense. 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 thatthe 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. How did DNA so rapidly become an irreplaceable tool in evolutionary biology? In this review we discuss the history of the molecular clock and the theory behind this unexpected and useful research tool. Weexamine how the observation of a molecular clock (a relatively constant rate of molecular change) has had two main effects on evolutionary biology. First, the constancy of rates has provided a window on the evolutionary process, by showing that molecular evolution is consistent with a neutral model rather than primarily driven by the action of natural selection. Second, because molecular change isexpected to accumulate steadily over time, it provides a new tool for investigating the evolutionary history of biological lineages (BOX 1). We also discuss the problems that plague the accuracy of molecular date estimates, and new techniques that have been designed to overcome these limitations.
www.nature.com/reviews/genetics

*Centre for the Study of Evolution, School of Biological Sciences,...