Evidence for Retrogene Origins of the Prion Gene Family

Abstract

The evolutionary origin of prion genes, only known to exist in the vertebrate lineage, had remained elusive until recently. Following a lead from interactome investigations of the murine prion protein, our previous bioinformatic analyses revealed the evolutionary descent of prion genes from an ancestral ZIP metal ion transporter. However, the molecular mechanism of evolution remained unexplored. Here we present a computational investigation of this question based on sequence, intron-exon, synteny and pseudogene analyses. Our data suggest that during the emergence of metazoa, a cysteine-flanked core domain was modularly inserted, or arose de novo, in a preexisting ZIP ancestor gene to generate a prion-like ectodomain in a subbranch of ZIP genes. Approximately a half-billion years later, a genomic insertion of a spliced transcript coding for such a prion-like ZIP ectodomain may have created the prion founder gene. We document that similar genomic insertions involving ZIP transcripts, and probably relying on retropositional elements, have indeed occurred more than once throughout evolution.

The ZIP5 Ectodomain Co-Localizes with PrP and May Acquire a PrP-Like Fold That Assembles into a Dimer

“…ZIP6 and ZIP10, together with their phylogenetically closest paralog ZIP5 (Slc39a5), are members of the LIV-1 subfamily of ZIP zinc transporters (LZTs) that are characterized by a conserved sequence motif found in transmembrane domain V [6] and the presence of N-terminal ectodomains absent in non-LZT members of this protein family. The mechanism of evolution of the PrP founder gene from an ancestral LZT gene was most likely based on a retrotransposition event that led to a loss of sequences coding for the C-terminal multi-spanning transmembrane domain present in LZTs [7]. Consequently, the similarity between PrP and LZT sequences is restricted to the N-terminal ectodomains of LZTs.…”

A ZIP6-ZIP10 heteromer controls NCAM1 phosphorylation and integration into focal adhesion complexes during epithelial-to-mesenchymal transition

“…More specifically, the PrP founder gene can be traced to an evolutionary event that occurred during vertebrate speciation. Mechanistically, it can be deduced to have involved the retro-insertion of a spliced and C-terminally truncated transcript of an ancestral ZIP transporter with similarity to ZIP6 and ZIP108. Intriguingly, these discoveries were preceded by independent observations, which indicated that both morpholino-based knockdown (kd) of ZIP69 or PrP10 cause a similar gastrulation arrest phenotype in zebrafish embryos.…”

The prion protein family

“…13 for review). These three loci probably derived by retro-transposition of an ancestral ZIP metal ion transporter gene 14 . Doppel and Shadoo were demonstrated to be of neurological relevance.…”