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Human mutation rate revealed

August 27, 2009 By Elie E Dolgin This article courtesy of Nature News.

Next-generation sequencing provides the most accurate estimate to date.

Every time human DNA is passed from one generation to the next it accumulates 100–200 new mutations, according to a DNA-sequencing analysis of the Y chromosome.

This number — the first direct measurement of the human mutation rate — is equivalent to one mutation in every 30 million base pairs, and matches previous estimates from species comparisons and rare disease screens.

The British-Chinese research team that came up with the estimate sequenced ten million base pairs on the Y chromosome from two men living in rural China who were distant relatives. These men had inherited the same ancestral male-only chromosome from a common relative who was born more than 200 years ago. Over the subsequent 13 generations, this Y chromosome was passed faithfully from father to son, albeit with rare DNA copying mistakes.

The researchers cultured cells taken from the two men, and using next-generation sequencing technologies found 23 candidate mutations. Then they validated twelve of these mutations using traditional sequencing techniques. Eight of these mutations, however, had arisen in their cell-culturing process, which left just four genuine, heritable mutations. Extrapolating that result to the whole genome gives a mutation rate of around one in 30 million base pairs.

"It was very reassuring that our application of the new sequencing technologies seems to give a reliable result and that the number we've been using for the mutation rate is pretty much the right one," says Chris Tyler-Smith of the Wellcome Trust Sanger Institute in Hinxton, UK, who led the study, published today in Current Biology1.

Tyler-Smith says that direct measurement of the mutation rate can be used to infer events in our evolutionary past, such as when humans first migrated out of Africa, more accurately than previous methods. But before that's possible, researchers will need a more precise estimate, notes Laurent Duret, an evolutionary biologist at the University of Lyon in France. "The confidence interval for the mutation rate is still quite wide," he says. Sequencing more pairs of Y chromosomes from distant male cousins in other families should provide a more robust measurement and reveal how mutation rates vary between individuals, Duret adds.

Most of the Y chromosome doesn't mix with any other chromosomes, which makes estimating its mutation rate easier. But the mutation rate might be somewhat different on other chromosomes, points out Adam Eyre-Walker, an evolutionary biologist at the University of Sussex in Brighton, UK. Other projects that involve sequencing parents and their offspring, such as the 1000 Genomes Project, should start to illuminate how DNA changes across the rest of the genome.

"I'm sure this is just the first of many papers that will be doing the same sort of thing," says Tyler-Smith.


  1. Xue, Y. et al. Curr. Biol. 19, 1-5 (2009).


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