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Beyond polymorphisms: Genome scans and prion disease in mice
Edward R. Winstead

British researchers have identified three regions of the mouse genome associated with the incubation period of prion diseases. Hotspots on chromosomes 2, 11, and 12 may influence the development of prion disease in mice, according to a paper in Proceedings of the National Academy of Sciences.

Elizabeth M. C. Fisher, of the Department of Neurogenetics, Imperial College School of Medicine at St Mary's, London, led the study. Incubation times for Creutzfeldt-Jakob disease, a human variant of mad cow disease, and other prion diseases vary. This variation has been linked to polymorphisms in the prion protein gene in humans, mice and sheep. Fisher and colleagues now show that other factors also influence incubation times in mice.

"We have demonstrated unequivocally that genetic loci other than the [prion protein gene] can have a major effect on prion disease incubation time in mice," the researchers write. A total of eight potential hotspots were identified in the mouse genome.

The researchers scanned the genomes of 1,000 crossbred mice derived from strains that develop prion diseases at different rates. The incubation times were determined for all mice, which had been 'given' a form of prion disease. In the study's first phase, the researchers screened 400 mice; the resulting data led to a new set of genetic markers used to analyze the remaining 600 animals.

The ultimate goal is to characterize the chromosome regions, which may contain multiple factors, and to identify corresponding regions of the human genome. Fisher and colleagues note: "The identification of [candidate chromosome regions] for prion disease incubation time cast doubt on the validity of the genetic models used in current epidemiological studies, which may result in overly optimistic predictions of the size of the [variant Creutzfeldt-Jakob disease] epidemic."

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Lloyd, S.E. et al. Identification of multiple quantitative trait loci linked to prion disease incubation period in mice. Proc Natl Acad Sci USA 98, 6279-6283 (May 22, 2001).

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