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Genetic control of prion incubation period in mice
G A Carlson1, D Westaway, P A Goodman
1Jackson Laboratory, Bar Harbor, Maine 04609.
Abstract:
The prion gene complex (Prn) is located on mouse chromosome 2 between the beta-2-microglobulin (B2m) and agouti (A) genes. Within this complex are the prion protein gene (Prn-p), which encodes the only identified macromolecule (PrP) that purifies with infectious scrapie agent, and a scrapie incubation time gene (Prn-i). Using a variety of restriction endonucleases, six allelic forms of the Prn-p gene have been distinguished by their patterns of restriction fragment length polymorphisms. We had previously shown that the exceptionally long scrapie incubation period of I/LnJ mice inoculated with the Chandler isolate (over 200 days) was due to the effects of a scrapie incubation time gene tightly linked to Prn-p. So far, this long scrapie incubation time allele has been found only in those inbred mouse strains (I/LnJ, P/J and IM) that have the b allele of Prn-p. It is not known whether the incubation time gene and prion protein gene are two distinct loci or are one and the same. Putative recombinants between the incubation time phenotype and Prn-p genotype have been observed, but this could be due to effects of other genes segregating in the population. Regardless of whether or not the incubation time and PrP genes are identical, if any differences were found in the amino acid sequences of PrP encoded by the different Prn-p alleles there would be important implications for interpretation of results on 'strains' of scrapie agent. It would not be necessary to invoke nucleic acid as the informational macromolecule of the scrapie agent because differences in prion 'strains' recovered from mice with different Prn-p genotypes need not be the result of host selection but could be due to differences in host-encoded PrP.
Insights
The prion gene complex (Prn) in mice influences scrapie incubation times. Researchers investigated if the prion protein gene (Prn-p) and scrapie incubation time gene (Prn-i) are distinct or the same, impacting prion strain interpretation.
Area of Science:
- Genetics
- Neuroscience
- Molecular Biology
Background:
- The prion gene complex (Prn) on mouse chromosome 2 contains the prion protein gene (Prn-p) and a scrapie incubation time gene (Prn-i).
- The Prn-p gene encodes the prion protein (PrP), a key component associated with the infectious scrapie agent.
- A specific allele of Prn-p (Prn-p^b) is linked to a gene (Prn-i) conferring exceptionally long scrapie incubation periods in certain mouse strains.
Purpose of the Study:
- To investigate the genetic relationship between the prion protein gene (Prn-p) and the scrapie incubation time gene (Prn-i).
- To determine if these two genes are distinct loci or a single gene.
- To explore the implications of Prn-p allelic variations on the interpretation of prion 'strains'.
Main Methods:
- Analysis of restriction fragment length polymorphisms (RFLPs) to distinguish allelic forms of the Prn-p gene.
- Phenotypic analysis of scrapie incubation times in different mouse strains.
- Observation of potential recombinant events between Prn-p genotype and incubation time phenotype.
Main Results:
- Six allelic forms of the Prn-p gene were identified using RFLPs.
- A long scrapie incubation time allele (Prn-i) was found exclusively in mouse strains with the Prn-p^b allele.
- Putative recombinants suggest a possible separation between Prn-p and Prn-i, though other genetic factors could be involved.
Conclusions:
- The genetic linkage between Prn-p and Prn-i is strong, but their precise relationship (distinct loci vs. single gene) remains uncertain.
- Differences in host-encoded PrP, stemming from Prn-p allelic variations, could explain prion 'strains' without invoking a nucleic acid-based agent.
- This finding has significant implications for understanding prion diseases and the nature of the infectious agent.