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Microsatellite Study Provides Window on New Human Mutations

NEW YORK (GenomeWeb News) – A new study online in Nature Genetics is providing further details about the nature and frequency of new mutations in the human genome.

"Mutations are the raw material of evolution but have been difficult to study directly," the study's authors explained, calling the new work "the largest study of new mutations to date."

The American and Icelandic research team — led by Harvard University geneticist David Reich and Decode Genetics' Kari Stefansson, the company's founder and CEO — characterized new mutation patterns using microsatellite data for more than 85,000 Icelanders. In addition to determining the rate of new mutations per generation, the investigators uncovered an over-representation of alterations that could be traced back to fathers. And, similar to a study published earlier this week, the frequency of these mutations appeared to increase with paternal age, albeit at a more modest rate.

From the overall microsatellite-based mutation rate, which appears to be slightly higher than the mutation rate discerned from sequence data, the team estimated that humans and chimpanzees split from one another between 5.8 million and 9.77 million years ago and became distinct species in the two to three million years that followed.

Reich, Stefansson, and colleagues brought together microsatellite data for 85,289 Icelandic individuals belonging to almost 25,000 parent-child trios.

By looking at the 2,477 autosomal, polymorphic microsatellites, which had been tested for a previous linkage study, the investigators were able to tally up new germline mutations produced by DNA polymerase missteps.

Through analyses of parent-child trios and of families with more than one child and/or one generation included in the study, the team tracked down 2,058 new germline mutations.

Far more of these mutations seemed to stem from germline changes occurring in fathers than in mothers, they found, with paternal changes outweighing maternal changes by a ratio of more than three to one.

Consistent with patterns that researchers from Decode Genetics and elsewhere described earlier this week in Nature, the team found that the rate of new mutations increased in children of older fathers, but not of older mothers.

In the current study, for instance, researchers saw microsatellite patterns pointing to a doubling in mutation rates in children of 58-year-old fathers compared to those born to 20-year-old fathers. The paternal effect detected was somewhat more subtle than that described by the Decode-led team, which estimated a doubling in de novo mutations every 16.5 years — a discrepancy that authors of the new study speculated may be due to differences in the type of data and analyses used.

Along with effects related to mutations in the paternal germline, the team found differences in the frequency and nature of the new mutations that corresponded to a range of microsatellite features, including length, location, and repeat number.

More generally, the study authors noted that having the ability to do more detailed assessments of human mutation rates from genetic data could eventually curtail reliance on fossil data for determining the timing of some historical, evolutionary events.

For instance, by folding in whole genome sequence data for nearly two-dozen individuals genotyped at microsatellites, researchers came up with a per base, per generation mutation rate that allowed them to peg the human-chimpanzee speciation event to between 3.7 and 6.6 million years ago.

"Our direct estimation of the microsatellite mutation rate, combined with comparative genomics data, also allows us to estimate the data of human-chimpanzee speciation," they wrote, "which we define as the date of the last gene flow between human and chimpanzee ancestors."

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