Disparate evolution of prion protein domains and the distinct origin of Doppel‐ and prion‐related loci revealed by fish‐to‐mammal comparisons

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Abstract
SPECIFIC AIMSOur current understanding of prion biology and disease is largely based on studies performed on mammals, yet basic questions about the physiological function of prion proteins (PrPs) and the molecular nature of prion disorders remain elusive. To facilitate the establishment of non-mammalian models for prion research, we characterized the sequence, structural, and genomic homology between fish and other vertebrate PrPs, and analyzed the distinct molecular mechanisms that shaped the evolution of vertebrate PrP domains.PRINCIPAL FINDINGS1. Teleost fish possess duplicated PrPs, which are the genetic, structural, and syntenic homologues of mammalian PrP and doppelWe provide new sequence data documenting the existence of two orthologous PrP loci in bony fish (PrP-1 and -2), which display extensive variation in their length and amino acid composition, and which are highly expressed in adult and developing fish brains. Despite the low sequence similarity with their mammalian counterparts, fish PrPs s...