International Mammalian Genome Society

The 16th International Mouse Genome Conference (2002)


T Van Agtmael
MRC Human Genetics Unit

1) Manolakou K, 2) Beaton J, 2) McConnell I, 2) Farquar C, 2) Manson J, 1) Hastie ND, 2) Bruce M, 1) Jackson IJ
1) MRC Human Genetics Unit, 2) Institute of Animal Health

The incubation period (IP) and neuropathology of transmissible spongiform encephalopathies (TSEs) have been extensively used to distinguish prion isolates (or strains) inoculated into panels of inbred mouse strains. Such studies have shown that the BSE agent is indistinguishable from the agent causing variant Creutzfeldt-Jakob disease, but differs from isolates of sporadic CJD, reinforcing the idea that vCJD in Britain results from consumption of contaminated beef products. We present a mouse model for genes that modify the incubation period of BSE following cross-species transmission. We have used two mouse strains, C57BL and RIII, that carry the same prion protein (Pnrp) allele, but display a 100-day difference in their mean IP following intracerebral inoculation with primary BSE isolate. QTL analysis identified four different chromosomal loci which affect IP. These are different from QTLs identified by other groups studying other prion models; which may due to differences in protocols between the experiments, including the different TSE agents used and the different mouse strains.Many QTLs are a result of variation in expression of genes affecting the trait. We have used cDNA and oligonucleotide microarrays to compare gene expression in the spleen and brains of C57 and RIII animals. We have identified a number of genes that show consistent differences in expression. Genes that map within the chromosomal regions defined by QTL analysis are candidates for genes whose expression modifies BSE incubation period in mice.  BAC transgenics will be employed to analyse the effects of the candidate genes on the IP.

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