Figure 1. Schematic diagrams illustrating two alternative hypotheses on origin of prion mutations.

(A) The “cloud” hypothesis proposes that prion isolates are intrinsically heterogeneous and consists of major (red) and minor (various colors) PrP^Sc variants. Changes in the replication environment might provide selective advantages for replication of a minor variant leading to transformation of the PrP^Sc population. (B) The deformed templating model postulates that diverse structural variants are generated as a result of changes in replication environment via numerous PrP^Sc-dependent trial-and-error seeding events. A newly generated variant that fits better than parent PrP^Sc to the altered environment replaces the original PrP^Sc variant.