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Sanger-Led Team Refines Human DNA Mutation Rate Estimates

NEW YORK (GenomeWeb News) – In a paper appearing online yesterday in Current Biology, British and Chinese researchers reported that they have refined the estimates for human DNA mutation rates.

The team, led by investigators at the Wellcome Trust Sanger Institute, used a combination of high-throughput and Sanger sequencing to hone in on base substitutions in the same Y chromosome sequence from two distantly related men.

After tossing out false positives and mutations that had popped up in the cell lines, the researchers were left with four substitutions in the roughly 10 million bases of DNA they tested. Over the 13 generations separating the two men tested, that translates into about one base substitution in every 30 million nucleotides per generation.

"The ability to reliably measure rates of DNA mutation means we can begin to ask how mutation rates vary between different regions of the genome and perhaps also between different individuals," senior author Chris Tyler-Smith, an evolutionary biologist at the Wellcome Trust Sanger Institute, said in a statement.

Nearly 75 years ago, noted physiologist J.S. Haldane estimated the human mutation rate at one in every 25 million or so nucleotides per generation, based on his studies of the hemophilia gene. Other studies, based on phenotype or sequence comparisons between closely related species such as humans and chimps, have put the base substitution rate in the human genome at around one in every 23 million to 63 million nucleotides per generation.

The researchers examined DNA sequences from lymphoblastoid cell lines generated from two distantly related Chinese men from the same village. The men, who were separated by 13 generations, belonged to a family that carries a Y-linked hearing impairment mutation.

Using Illumina paired-end sequencing, the team sequenced the same stretch of Y chromosome DNA — which was about 10.15 million base pairs long — to 11 times coverage for one of the men and 20 times coverage for the other.

When the researchers compared the Y chromosome sequence from the Chinese men with reference sequence from the same region, they found many possible base substitutions. But after removing false-positive mutations by comparing the sequences to SNPs identified by the Y Chromosome Consortium, the team was left with 23 potential mutations.

Of these, 18 were classified as "first-class" candidates (which were more likely to be true mutations) and another five were "second-class" candidates. A dozen of the first class candidates — but none of the second-class candidates — were verified by capillary sequencing.

And when the researchers compared these 12 potential mutations with sequences generated by capillary sequencing of blood samples provided by the two men and other members of their family, they concluded that four of the changes were genuine mutations. The other eight appear to have sprung up in the cell lines used for the initial sequencing study.

If that pattern carries over on a whole-genome scale, it translates into one base substitution in every 15 to 30 million nucleotides per generation — a rate that resembles that predicted by Haldane. "This was reassuring because the methods we used — harnessing next-generation sequencing technology — had not previously been tested for this kind of research," Tyler-Smith said in a statement.

The team cautioned that mutation rates are thought to vary in different parts of the genome, with the Y chromosome DNA likely undergoing more frequent base substitutions than DNA found on autosomal chromosomes.

But now that the team has shown that they can get clues about mutation rates by sequencing nuclear DNA from related individuals' mutation rates, they noted that sequencing more related individuals could further improve mutation rate estimates.

"[W]e have shown that one can use next-generation sequencing technology to measure the very low mutation rate of human nuclear DNA reliably," the authors concluded. "The mutation rate observed is consistent with that inferred from evolutionary comparisons but can potentially be measured more precisely and provide new insights into human mutation processes."

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