Abstract
BackgroundTransmissible Spongiform Encephalopathies (TSEs) are a group of progressive fatal neurodegenerative disorders, triggered by abnormal folding of the endogenous prion protein molecule. The encoding gene is a major biological factor influencing the length of the asymptomatic period after infection. It remains unclear the extent to which the variation between quantitative trait loci (QTLs) reported in mouse models is due to methodological differences between approaches or genuine differences between traits. With this in mind, our approach to identifying genetic factors has sought to extend the linkage mapping approach traditionally applied, to a series of additional traits, while minimising methodological variability between them. Our approach allows estimations of heritability to be derived, as well as predictions to be made about possible existence of genetic overlap between the various traits.Methodology/Principal FindingsOur data indicate a surprising degree of heritability (up to 60%). Correlations between traits are also identified. A series of QTLs on chromosomes 1, 2, 3, 4, 6, 11 and 18 accompany our heritability estimates. However, only a locus on chromosome 11 has a general effect across all 4 models explored.Conclusions/SignificanceWe have achieved some success in detecting novel and pre-existing QTLs associated with incubation time. However, aside from the general effects described, the model-specific nature of the broader host genetic architecture has also been brought into clearer focus. This suggests that genetic overlap can only partially account for the general heritability of incubation time when factors, such as the nature of the TSE agent and the route of administration are considered. This point is highly relevant to vCJD (a potential threat to public health) where the route of primary importance is oral, while the QTLs being sought derive exclusively from studies of the ic route. Our results highlight the limitations of a single-model approach to QTL-mapping of TSEs.
Highlights
The prion protein (Prnp) locus has long been established as the major genetic determinant of Transmissible Spongiform Encephalopathy (TSE) incubation time, its effects do not fully explain the variance associated with this trait, other critical factors must play an important role in the aetiology of these disorders [1], [2]
Me7 ic is the only trait for which QTLs are not detected, this reflects the low phenotypic variance observed in F2s
The heritability of age at onset and death for the human inherited TSE form was recently determined to be 0.55 [19]. This value is comparable to our own estimates which derive from a related phenotype and are the first to be reported for an acquired TSE (h2narrow sense range = 0.3 to 0.6)
Summary
The Prnp locus has long been established as the major genetic determinant of Transmissible Spongiform Encephalopathy (TSE) incubation time, its effects do not fully explain the variance associated with this trait, other critical factors must play an important role in the aetiology of these disorders [1], [2]. Prion research has benefitted from the success of linkage studies conducted in the mouse These have highlighted several regions associated with the incubation period phenotype [5]. It remains unclear the extent to which the variation between quantitative trait loci (QTLs) reported in mouse models is due to methodological differences between approaches or genuine differences between traits With this in mind, our approach to identifying genetic factors has sought to extend the linkage mapping approach traditionally applied, to a series of additional traits, while minimising methodological variability between them. Our approach allows estimations of heritability to be derived, as well as predictions to be made about possible existence of genetic overlap between the various traits
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