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In order to measure the base substitution mutation rate at the DFNY1 locus, the researchers cultured cells taken from two men who were distant relatives from the same Chinese family but separated by 13 generations. This particular family carries a mutation at the DFNY1 locus associated with Y-linked hearing impairment. The Y chromosome does not mix its DNA with other chromosomes through recombination during sexual reproduction, which makes it easier to estimate the mutation rate between generations. A 10.5 million base-pair region of the Y-chromosome containing this locus was sequenced and base substitutions catalogued. Alignment of these sequences against the reference Y chromosome sequence identified many more single nucleotide polymorphisms (SNPs) than expected; however, many of these were due to alignment and base-calling errors. In order to better identify candidate mutations, the SNPs were compared with those identified by the Y-Chromosome Consortium, resulting in a list of 23 candidate mutations. Twelve of these mutations were verified following traditional Sanger sequencing of DNA from cell lines; however, only four of these mutations were “true” as they were also present in blood DNA from the two men and their family members. The other mutations are thought to have subsequently occurred during cell culture.

Based on the number of mutations, the length of DNA examined and the number of generations separating the two men, the researchers were able to calculate the mutation rate as one mutation in every 15-30 million nucleotides. This corresponds to around 100-200 new mutations in the genome per generation (see Nature News).The study was conducted by an international team of researchers, including those at the Wellcome Trust Sanger Institute and is the first account of using next generation sequencing technologies to measure mutation rates (see press release).