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Darwinian Evolution of Prions in Cell Culture

Science  12 Feb 2010:
Vol. 327, Issue 5967, pp. 869-872
DOI: 10.1126/science.1183218

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DNA-less Evolution

Prions are proteinaceous infectious elements involved in a variety of neurodegenerative diseases, including scrapie in sheep and so-called mad cow disease in cattle. Now Li et al. (p. 869, published online 31 December) show that, when propagated in tissue culture cells, cloned prion populations become diverse by mutational events and can undergo selective amplification. Thus, even though devoid of a coding genome, prions, when propagated under a particular selection regime, can be subject to rapid evolution.

Abstract

Prions are infectious proteins consisting mainly of PrPSc, a β sheet–rich conformer of the normal host protein PrPC, and occur in different strains. Strain identity is thought to be encoded by PrPSc conformation. We found that biologically cloned prion populations gradually became heterogeneous by accumulating “mutants,” and selective pressures resulted in the emergence of different mutants as major constituents of the evolving population. Thus, when transferred from brain to cultured cells, “cell-adapted” prions outcompeted their “brain-adapted” counterparts, and the opposite occurred when prions were returned from cells to brain. Similarly, the inhibitor swainsonine selected for a resistant substrain, whereas, in its absence, the susceptible substrain outgrew its resistant counterpart. Prions, albeit devoid of a nucleic acid genome, are thus subject to mutation and selective amplification.

  • * These authors contributed equally to this work.

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