Prion's Progress: Patterns and Rates of Molecular Evolution in Relation to Spongiform Disease |
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Authors: | David C Krakauer Paolo M de A Zanotto Mark Pagel |
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Institution: | (1) Department of Zoology, University of Oxford, South Parks Road, Oxford OX1 3PS, UK, GB;(2) Discipline de Doencas Infeciosas e Parasitarias—DIPA, Universidade Federal de Sao Paulo, UNIEFESP, Sao Paulo, SP-Brazil, BR;(3) BBSRC-NERC Ecology & Behaviour Group, Department of Zoology, University of Oxford, South Parks Road, Oxford OX1 3PS, UK, GB |
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Abstract: | Modification of the cellular prion protein has been correlated with the acquisition of several neurodegenerative diseases,
including kuru, scrapie, bovine spongiform encephalopathy (BSE), and Creutzfeldt–Jakob disease (CJD). Sequence conservation
and amino acid identity are known to influence the efficacy of interspecific transmission. We analyzed patterns of interspecific
genetic variation with a view toward identifying features related to disease transmission. The reconstructed gene trees and
amino acid tree were compared with the species tree, and all discordances observed were related to the species barrier of
disease transmission. The rates of synonymous substitution, nonsynonymous substitution, and nucleotide content were determined
for the protein-coding gene. Substitutions implicated in each of the prion diseases were found to occur in regions of the
protein that are least variable across all species—opposite to the pattern of variability expected from interaction with an
infectious pathogen. Amino acid residues related to the species barrier form a single cluster associated with the first alpha-helical
domain of the protein. Residues related to sporadic and hereditary human prion disease form two separate clusters, associated
with the second and third alpha-helical domains. Taken together, these results are consistent with the view that prion diseases
arise from accidents in protein folding, rather than infection with an undiscovered virus-like particle. We speculate that
the differences in disease phenotype between transmissable and hereditary forms could result from interactions between different
parts of the protein during propagation.
Received: 18 April 1997 / Accepted: 17 October 1997 |
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Keywords: | : Prion evolution — Prion disease — Species barrier — Scrapie — Spongiform encephalopathy |
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