By Matthew Cobb

One of the most important tools in evolutionary biology over the last thirty or so years has been the development of the ‘molecular clock’, which is a technique for measuring how long ago two organisms (or taxa or species) separated on the ‘tree of life’. This approach has been incredibly powerful, and underlies much of our understanding of the rate of evolution, linking fossil and molecular data – all the figures from the excellent Timetree.org are based on the molecular clock. But now it appears that in our lineage at least, the clock may not have been ticking quite so fast as we thought, and some recalibration is going to be necessary.

The basic assumption behind the molecular clock is that mutations – changes in DNA – occur at a constant rate over time, and that the number of differences between two groups can therefore be turned into a figure based on the time since the two diverged. This phenomenon was first noticed in 1962 by Linus Pauling and Emile Zuckerkandl looking at differences in haemoglobin genes, then explicitly turned into a hypothesis the following year by Margoliash, before being fully developed in the 1970s by Allan Wilson. (It is in fact a bit more complicated, as the average generation time of a species has to be taken into account – the shorter the generation time, the higher the mutation rate.)

There are some important provisos to the clock – any stretch of DNA that is subject to selection, for example, is not going to be a very useful source of clock data, as genetic differences will tend to be removed by selection; many genes that are vital to organismal function are therefore highly conserved, showing few differences between groups. For this reason, scientists tend to use either ‘synonymous changes’ in DNA – these are ‘silent’ differences that do not cause any change in gene function (protein structure, gene regulation, or whatever) – or to use stretches of non-coding DNA, which appear to be not subject to natural selection and to evolve ‘neutrally’, just accumulating mutations with time.

The sources of spontaneous mutations are well-known – mistakes in the cellular machinery during copying of DNA, electromagnetic radiation, mutagenic chemicals (most of them completely natural), and so on. These spontaneous mutations are important not only for calibrating the clock, but above all for providing the raw material for evolution by natural selection. The whole infinite variety of life is the consequence of mutations, which have then been filtered through the sieve of natural selection, over vast periods of time.

The molecular clock has been particularly important in helping to calibrate and understand the wealth of fossils relating to human evolution that have been discovered over the past decades. In fact, fossil dates have been used to help calibrate the clock data, and as a result the mutation rate that has generally been used for humans and other apes has been about 1 mutation per year per billion bases of DNA. However, new results from massive programmes of DNA sequencing have revealed that this assumed rate is probably much higher than what has actually been taking place in our gonads.

A review by Aylwun Scally and Richard Durbin, recently published in Nature Reviews Genetics, reveals that over the last decade, nine studies have come out with substantially lower mutation rates, suggesting our clocks have been running far too fast. These studies have looked at mutation rates across the whole genome, and have focused on particular genes, including one study of over 14,000 people. They all suggest that the actual mutation rate is about half that previously estimated. To put this into perspective, a study of 78 families from Iceland (mother, father, child) found that on average, a baby has 36 spontaneous mutations that are not present in either parent. Depending on where you grew up – presence of natural radiation etc – the number of spontaneous mutations in your genes is probably not too far different.

So what happens when this new, lower, figure is plugged into our estimates of divergence times for the various twigs and branches on the tangled bank of recent human evolution? Because the clock is now thought to be ticking more slowly than we originally estimated, the divergence times are being put back. So, for example, the human/Neanderthal split was estimated at between 272,000-435,000 years ago. The new figure would appear to be something more like 400,000-600,000 years.

This removes an odd discrepancy, as previous estimates of human/Neanderthal divergence using mitochondrial DNA (mtDNA is found in the tiny mitochondria of our cells, which are inherited maternally, and which are involved only in the generation of energy) had come up with a figure 0f 500,000-600,000 years ago. So both nuclear DNA and mtDNA now give a similar estimate – we split from our Neanderthal cousins about half a million years ago. Not that that stopped us mating with them and getting some of their genes… In terms of the time when we left Africa (based on genetic differences between non-African and African populations), that figure used to be put at around 70,000 years ago; it now appears to have been substantially earlier, perhaps 90,000-130,000 years ago.

This useful table assembled by Ann Gibbons in her excellent Science magazine piece summarises the changes, and their links with the fossils:



A lot of unknowns remain – in particular the issue of estimating generation time in prehistoric populations, as well as the lack of population-level data for prehistoric groups (e.g. Neanderthals or Denisovans). But the increasing richness of molecular data are producing ever more refined estimates of our past. And that is the power of science – nothing is taken as fixed, knowledge changes and increases, in a uniquely progressive way, enabling us to revise and refine our understanding, and even to reject what we previously thought to be true. Indeed, there is grandeur in this view of life.

References (both hidden behind pay walls, sadly):

Aylwyn Scally and Richard Durbing (2012) Revising the human mutation rate: implications for the understanding human evolution. Nature Reviews Genetics 13:745-753.

Ann Gibbons (2012) Turning back the clock” slowing the pace of prehistory. Science 338:189-191.

You can also learn more by listening to the Science magazine podcast item about this.