Complete Genomic Sequence and Analysis of the Prion Protein Gene Region from Three Mammalian Species

The prion protein (PrP), first identified in scrapie-infected rodents, is encoded by a single exon of a single-copy chromosomal gene. In addition to the protein-coding exon, PrP genes in mammals contain one or two 5′-noncoding exons. To learn more about the genomic organization of regions surrounding the PrP exons, we sequenced 10 5 bp of DNA from clones containing human, sheep, and mouse PrP genes isolated in cosmids or λ phage. Our findings are as follows: (1) Although the human PrP transcript does not include the untranslated exon 2 found in its mouse and sheep counterparts, the large intron of the human PrP gene contains an exon 2-like sequence flanked by consensus splice acceptor and donor sites. (2) The mouse Prnp a but not the Prnp b allele found in 44 inbred lines contains a 6593 nucleotide retroviral genome inserted into the anticoding strand of intron 2. This intracisternal A-particle element is flanked by duplications of an AAGGCT nucleotide motif. (3) We found that the PrP gene regions contain from 40% to 57% genome-wide repetitive elements that independently increased the size of the locus in all three species by numerous mutations. The unusually long sheep PrP 3′-untranslated region contains a “fossil” 1.2-kb mariner transposable element. (4) We identified sequences in noncoding DNA that are conserved between the three species and may represent biologically functional sites. [The nucleotide sequence data reported in this paper have been submitted to the GenBank sequence database and have been assigned the accession numbers U29185 (human), U29186 (mouse), and U67922 (sheep).]