A method to help elucidate the role of short tandem repeats has been developed by a team that includes scientists from the University of California San Diego, New York Genome Center, Harvard University, and the Massachusetts Institute of Technology. The findings were published yesterday in Nature Genetics.
The paper is part of the ongoing, decades-long effort to pinpoint harmful mutations in the human genome. Tandem repeats are often overlooked in these efforts, and have sometimes been disregarded as junk DNA. But researchers led by Melissa Gymrek, an assistant professor at UC San Diego, believe that tandem repeats are likely to play key roles in human health and need to be studied in depth.
Tandem repeats are difficult to analyze with current genome sequencing techniques. That difficulty prompted the team to create a mathematical model that predicts how frequently and in what way the repeats appear and mutate in the human genome. The new algorithm was based on a method called MUTEA, which was previously developed to precisely estimate individual mutation rates for tandem repeats on the Y chromosome. The algorithm was modified so it would analyze pairs of haplotypes.
The key insight the method provided is that different classes of mutations happen at regular, predictable intervals in time, constituting a “molecular clock”. This clock can be used to determine how often mutations occur within a genome.
The researchers also used the model to calculate actual mutation rates and compare those to expected mutation rates. The team used their model on a number of different tandem repeats related to both late and early onset conditions, such as limb malformations. The model correctly identified that repeats involved in early-onset conditions were subject to constraint. They calibrated their method by using a set of tandem repeats that are not associated with specific conditions, which the FBI uses to identify people. As expected, these repeats mutate at the expected rate and are not constrained.