DNA mutation clock proves tough to set

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Human mutations are not just a favourite device in science-fiction films such as the X-men series, they also offer a way to mark time in the evolutionary past.

Mathematicians keep refining even though they know it to more than 12trillion digits; physicists beat themselves up because they cannot pin down the gravitational constant beyond three significant figures. Geneticists, by contrast, are having trouble deciding between one measure of how fast human DNA mutates and another that is half that rate.

The rate is key to calibrating the molecular clock that puts DNA-based dates on events in evolutionary history. So at an intimate meeting in Leipzig, Germany, on 2527 February, a dozen speakers puzzled over why calculations of the rate at which sequence changes pop up in human DNA have been so much lower in recent years than previously. They also pondered why the rate seems to fluctuate over time. The meeting drew not only evolutionary geneticists, but also researchers with an interest in cancer and reproductive biology fields in which mutations have a central role.

Mutation is ultimately the source of all heritable diseases and all biological adaptations, so understanding the rate at which mutations evolve is a fundamental question, says Molly Przeworski, a population geneticist at Columbia University in New York City who attended the Human Mutation Rate Meeting.

Researchers tried to put a number on the human mutation rate even before they knew that genetic information is encoded in DNA. In the 1930s, pioneering geneticist J.B.S.Haldane came up with a good estimate by measuring how the mutations responsible for haemophilia appeared in extended families.

Later estimates of the mutation rate counted the differences between stretches of DNA and protein amino-acid sequences in humans and those in chimpanzees or other apes, and then divided the number of differences by the time that has elapsed since the species most recent common ancestor appeared in the fossil record. These estimates were clouded by the patchiness of the fossil record, but researchers eventually settled on a consensus: each DNA letter, on average, mutates once every billion years. That is a suspiciously round number, molecular anthropologist Linda Vigilant of the Max Planck Institute for Evolutionary Anthropology in Leipzig told Nature in 2012 (see Nature 489, 343344; 2012).

In the past six years, more-direct measurements using next-generation DNA sequencing have come up with quite different estimates. A number of studies have compared entire genomes of parents and their children and calculated a mutation rate that consistently comes to about half that of the last-common-ancestor method.

A slower molecular clock worked well to harmonize genetic and archaeological estimates for dates of key events in human evolution, such as migrations out of Africa and around the rest of the world1. But calculations using the slow clock gave nonsensical results when extended further back in time positing, for example, that the most recent common ancestor of apes and monkeys could have encountered dinosaurs. Reluctant to abandon the older numbers completely, many researchers have started hedging their bets in papers, presenting multiple dates for evolutionary events depending on whether mutation is assumed to be fast, slow or somewhere in between.

Last year, population geneticist David Reich of Harvard Medical School in Boston, Massachusetts, and his colleagues compared the genome of a 45,000-year-old human from Siberia with genomes of modern humans and came up with the lower mutation rate2. Yet just before the Leipzig meeting, which Reich co-organized with Kay Prfer of the Max Planck Institute for Evolutionary Anthropology, his team published a preprint article3 that calculated an intermediate mutation rate by looking at differences between paired stretches of chromosomes in modern individuals (which, like two separate individuals DNA, must ultimately trace back to a common ancestor). Reich is at a loss to explain the discrepancy. The fact that the clock is so uncertain is very problematic for us, he says. It means that the dates we get out of genetics are really quite embarrassingly bad and uncertain.

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DNA mutation clock proves tough to set