It's with thanks to noted chemist-blogger Derek Lowe that I discovered a recent paper that (once again) has me questioning one of the cornerstones of 21st century biology. I am talking about our over-reliance on the inbred mouse as a proxy for all things human health and disease. The paper, "Passenger Mutations Confound Interpretation of All Genetically Modified Congenic Mice," was published last month in Immunity.
The authors combed through a database of mouse genetic variation, looking to see whether mice that had had genes inactivated (knockouts) or inserted (transgenic) really were identical to so-called wild type mice. What they found was that the process which we use to genetically modify mice doesn't just affect the genes we add or subtract. Instead, genes near the one you’re targeting may have naturally occurring variations or get damaged during the process. These variations will stay with your targeted gene as you breed it into other mouse strains in order to do experiments—the titular 'passenger mutations.'
That's something that researchers rarely account for, and those passenger mutations can confound our studies. So, it may be that a mouse missing gene A might be widely used as a model for disease X. But all the while, an unnoticed mutation in gene B is actually responsible for the phenotype or drug effect being investigated.
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