Identification of multiple quantitative trait loci linked to prion disease incubation period in mice

Sarah E. Lloyd, Obia N. Onwuazor, Jonathan A. Beck, Gary Mallinson, Martin Farrall, Paul Targonski, John Collinge, Elizabeth M C Fisher

Research output: Contribution to journalArticle

163 Citations (Scopus)

Abstract

Polymorphisms in the prion protein gene are known to affect prion disease incubation times and susceptibility in humans and mice. However, studies with inbred lines of mice show that large differences in incubation times occur even with the same amino acid sequence of the prion protein, suggesting that other genes may contribute to the observed variation. To identify these loci we analyzed 1,009 animals from an F2 intercross between two strains of mice, CAST/Ei and NZW/OlaHSd, with significantly different incubation periods when challenged with RML scrapie prions. Interval mapping identified three highly significantly linked regions on chromosomes 2, 11, and 12; composite interval mapping suggests that each of these regions includes multiple linked quantitative trait loci. Suggestive evidence for linkage was obtained on chromosomes 6 and 7. The sequence conservation between the mouse and human genome suggests that identification of mouse prion susceptibility alleles may have direct relevance to understanding human susceptibility to bovine spongiform encephalopathy (BSE) infection, as well as identifying key factors in the molecular pathways of prion pathogenesis. However, the demonstration of other major genetic effects on incubation period suggests the need for extreme caution in interpreting estimates of variant Creutzfeldt-Jakob disease epidemic size utilizing existing epidemiological models.

Original languageEnglish (US)
Pages (from-to)6279-6283
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume98
Issue number11
DOIs
StatePublished - May 22 2001
Externally publishedYes

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Prion Diseases
Quantitative Trait Loci
Prions
Bovine Spongiform Encephalopathy
Scrapie
Chromosomes, Human, Pair 12
Chromosomes, Human, Pair 11
Creutzfeldt-Jakob Syndrome
Chromosomes, Human, Pair 6
Chromosomes, Human, Pair 7
Chromosomes, Human, Pair 2
Human Genome
Genes
Amino Acid Sequence
Alleles
Infection

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Identification of multiple quantitative trait loci linked to prion disease incubation period in mice. / Lloyd, Sarah E.; Onwuazor, Obia N.; Beck, Jonathan A.; Mallinson, Gary; Farrall, Martin; Targonski, Paul; Collinge, John; Fisher, Elizabeth M C.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 98, No. 11, 22.05.2001, p. 6279-6283.

Research output: Contribution to journalArticle

Lloyd, SE, Onwuazor, ON, Beck, JA, Mallinson, G, Farrall, M, Targonski, P, Collinge, J & Fisher, EMC 2001, 'Identification of multiple quantitative trait loci linked to prion disease incubation period in mice', Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 11, pp. 6279-6283. https://doi.org/10.1073/pnas.101130398
Lloyd, Sarah E. ; Onwuazor, Obia N. ; Beck, Jonathan A. ; Mallinson, Gary ; Farrall, Martin ; Targonski, Paul ; Collinge, John ; Fisher, Elizabeth M C. / Identification of multiple quantitative trait loci linked to prion disease incubation period in mice. In: Proceedings of the National Academy of Sciences of the United States of America. 2001 ; Vol. 98, No. 11. pp. 6279-6283.
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