PRION PROTEIN GENE VARIATION AMONG PRIMATES

Prion diseases are manifest as genetic, sporadic or infectious neurode generative disorders in humans and animals. The prolonged incubation t imes that accompany the transmission of prions between species are due , at least in part, to differences in prion protein (PrP) sequence. To examine the species barriers between non-human primates and humans, w e sequenced the open reading frames (ORF) of 25 PrP genes from apes an d monkeys. Comparison of the PrP genes of these animals with that of h umans showed amino acid identities ranging from 92.9 to 99.6%. While p hylograms of primate PrP sequences revealed a novel branching pattern for the apes, the genomic organization of all the primate PrP genes wa s similar, with the entire ORF contained within a single exon. Alignme nt of variant residues in primates, rodents and domestic animals showe d no concordance with the mutations that segregate with human prion di seases or with polymorphisms that modulate disease in humans, mice and sheep. Most substitutions were conservative and, characteristically, clustered outside the four putative alpha-helical regions that are tho ught to form a four-helix bundle in the cellular isoform of PrP (PrPC) . Deletion of one of five Gly-Pro rich octarepeats from the N-terminus of PrP was seen in some species, while squirrel monkeys had an additi onal octarepeat; squirrel monkeys have been frequently used as experim ental hosts for transmission of human prions. Alignment of primate and other mammalian PrP sequences suggests that codons between 90 and 130 have a profound influence on the transmissibility of prions from one species to another.