Abstract
BackgroundThe homologues of human disease genes are expected to contribute to better understanding of physiological and pathogenic processes. We made use of the present availability of vertebrate genomic sequences, and we have conducted the most comprehensive comparative genomic analysis of the prion protein gene PRNP and its homologues, shadow of prion protein gene SPRN and doppel gene PRND, and prion testis-specific gene PRNT so far.ResultsWhile the SPRN and PRNP homologues are present in all vertebrates, PRND is known in tetrapods, and PRNT is present in primates. PRNT could be viewed as a TE-associated gene. Using human as the base sequence for genomic sequence comparisons (VISTA), we annotated numerous potential cis-elements. The conserved regions in SPRNs harbour the potential Sp1 sites in promoters (mammals, birds), C-rich intron splicing enhancers and PTB intron splicing silencers in introns (mammals, birds), and hsa-miR-34a sites in 3'-UTRs (eutherians). We showed the conserved PRNP upstream regions, which may be potential enhancers or silencers (primates, dog). In the PRNP 3'-UTRs, there are conserved cytoplasmic polyadenylation element sites (mammals, birds). The PRND core promoters include highly conserved CCAAT, CArG and TATA boxes (mammals). We deduced 42 new protein primary structures, and performed the first phylogenetic analysis of all vertebrate prion genes. Using the protein alignment which included 122 sequences, we constructed the neighbour-joining tree which showed four major clusters, including shadoos, shadoo2s and prion protein-likes (cluster 1), fish prion proteins (cluster 2), tetrapode prion proteins (cluster 3) and doppels (cluster 4). We showed that the entire prion protein conformationally plastic region is well conserved between eutherian prion proteins and shadoos (18–25% identity and 28–34% similarity), and there could be a potential structural compatibility between shadoos and the left-handed parallel beta-helical fold.ConclusionIt is likely that the conserved genomic elements identified in this analysis represent bona fide cis-elements. However, this idea needs to be confirmed by functional assays in transgenic systems.
Highlights
The homologues of human disease genes are expected to contribute to better understanding of physiological and pathogenic processes
The contiguity between SPRN and distal genes encoding GTP-binding protein GTP and peroxisomal amine-oxidase PAOX is conserved between vertebrates (Figure 1A), as known for eutherians and pufferfish [11,13]
2.2.2 Conserved regions in PRNP promoters, introns and 3'UTRs Using VISTA comparisons, we identified 7 conserved regions in the PRNP upstream intergenic regions, 5 conserved regions in the provisional PRNP promoters, 15 conserved regions in the PRNP introns and 5 conserved regions in the PRNP 3'-UTRs
Summary
The homologues of human disease genes are expected to contribute to better understanding of physiological and pathogenic processes. The prion diseases are fatal neurodegenerative diseases in humans and animals, which manifest as infectious, inherited and sporadic [1]. The common feature of prion diseases is aberrant metabolism of prion protein PrP. PrP may exist as a heterogenous mix of topological isoforms PrPC and may fold into the compact conformation enciphering features of prions PrPSc [[1,2,3] and V. PrPC may act both pro- and anti-apoptotically, and PrPSc could have a role in the cellular metabolism as well [[2,4] and V. PrP could act as a growth factor in the neuronal context [5]
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