Philip Gerrish

Mutators, defined as variants with an increased mutation rate, are known co-conspirators in things like cancer and the evolution of antibiotic resistance. Mutators themselves are produced by mutation, often in genes like mismatch repair genes and polymerase genes. But the problem is that there are lots of such genes and it is quite possible, even probable, that mutators can arise by mutation in other genes that we don't know about. In other words, the mutational target for mutators is large and incompletely known. So a mutator-mutation rate can't be estimated by brute-force sequencing methods, i.e., it cannot be directly observed and is therefore an inherently hidden or latent parameter. Here, we develop a method to estimate the mutator-mutation rate based only on numbers of observable mutations. The math is fun but the feasibility of the experimental protocol deriving from our "first-order" math is questionable. This is where you come in! We need creative ideas. I hope the talk sparks some fruitful conversation. A couple cancer groups are already interested but deterred a bit by these experimental hurdles.