The Tre2 ( USP6 ) oncogene is a hominoid-specific gene

Abstract

Gene duplication and domain accretion are thought to be the major mechanisms for the emergence of novel genes during evolution. Such events are thought to have occurred at early stages in the vertebrate lineage, but genomic sequencing has recently revealed extensive amplification events during the evolution of higher primates. We report here that the Tre2 (USP6) oncogene is derived from the chimeric fusion of two genes, USP32 (NY-REN-60), and TBC1D3. USP32 is an ancient, highly conserved gene, whereas TBC1D3 is derived from a recent segmental duplication, which is absent in most other mammals and shows rapid amplification and dispersal through the primate lineage. Remarkably, the chimeric gene Tre2 exists only in the hominoid lineage of primates. This hominoid-specific oncogene arose as recently as 21-33 million years ago, after proliferation of the TBC1D3 segmental duplication in the primate lineage. In contrast to the broad expression pattern of USP32 and TBC1D3, expression of Tre2 is testis-specific, a pattern proposed for novel genes implicated in the emergence of reproductive barriers. The sudden emergence of chimeric proteins, such as that encoded by Tre2, may have contributed to hominoid speciation.

The Primate-specific Protein TBC1D3 Is Required for Optimal Macropinocytosis in a Novel ARF6-dependent Pathway

“…Importantly, the gene structure of TBCID3 and RNTRE is extremely well conserved, even when compared with a distant RNTRE ortholog, such as the Xenopus tropicalis RNTRE ( Figure 1B). This suggests that the recent origin of TBCID3, during primate speciation (Paulding et al, 2003), is due to a duplication of the RNTRE locus. Accordingly, all TBCID3-coding exons are identical in length to those of RNTRE, with the exception of the last one, which also contains the 3Ј untranslated regions (UTRs; Figure 1B and Figure S1 in Supplementary Material).…”

“…Gene structure conservation is a common feature among ortholog and paralog genes, and it has been proposed to represent a record of key events in evolution, even when protein sequence similarity is low (Batzoglou et al, 2000;Betts et al, 2001;Koonin, 2005). This applies to TBC1D3, which despite having originated only after the initial primate radiation (ϳ60 million years ago; Paulding et al, 2003), accumulated, in a remarkably short period of time, a considerable number of mutations, accounting for the relatively low degree of similarity between the TBC1D3 and RNTRE gene products ( Figure S2 in Supplementary Material). This also suggests that TBC1D3 has been subject to positive evolutionary pressure, likely resulting in the acquisition of novel functions with respect to RNTRE.…”

“…Little is known, instead, about TBC1D3. Because the TBC1D3 gene originated during primate speciation (Paulding et al, 2003), we reasoned that studies of its function might provide a unique opportunity to understand how the machinery of membrane traffic and endocytosis contributes to evolution. Thus, the present studies were undertaken to understand the biological function of TBC1D3.…”

USP6 (Tre2) Fusion Oncogenes in Aneurysmal Bone Cyst

“…CDH11 is expressed strongly in mesenchymal cells, particularly those of osteoblastic differentiation, whereas USP6 expression is expressed predominantly in germ cells (10,11). These known expression profiles, together with the genomic FISH localizations, were most consistent with fusion oncogenes composed of the CDH11 5Ј untranslated region and the entire USP6 coding sequence.…”

USP6 oncogene promotes Wnt signaling by deubiquitylating Frizzleds

“…Thus, USP6 and USP8 may possess both redundant and unique functions in regulating trafficking and Wnt signaling, with cell type and subcellular localization of both the USPs and cargoes contributing to their specificity. In this context, it is important to note that the USP6 gene only exists in hominoids, and thus cannot readily be studied in model organisms (36).…”