Evolution of Cyclophilin A and TRIMCyp Retrotransposition in New World Primates

Abstract

Host cell factors modulate retroviral infections. Among those, cyclophilin A (CypA) promotes virus infectivity by facilitating virus uncoating or capsid unfolding or by preventing retroviral capsid interaction with cellular restriction factors. In Aotus species, a retrotransposed copy of CypA inserted into the tripartite motif 5 (TRIM5) gene encodes a fusion protein which may block human immunodeficiency virus type 1 by targeting the incoming virus to ubiquitin-ligated degradation or by interfering with normal uncoating of the incoming particle, rendering those monkeys resistant to infection. In this study, we have extensively analyzed representative specimens from all New World primate genera and shown that the retrotransposed CypA copy is only present in Aotus. We have shown that this inserted copy diverged from its original counterpart and that this occurred prior to Aotus radiation, although no positive selection was observed. Finally, our data underscores the need for a precise taxonomic identification of primate species used as models for retroviral infections and novel antiviral approaches.

Genome of the Chinese tree shrew

“…S11) as it has achieved five Trim5 copies with four encoding validated open reading frames by several lineage-specific tandem duplication events. Astonishingly, similar to some primates 46,47 , one of the TRIM5 copy has a CypA retrotranposition and form a TrimCyp chimera transcript, which was validated by reverse transcriptase PCR (Supplementary Fig. S12).…”

Birth, decay, and reconstruction of an ancient TRIMCyp gene fusion in primate genomes

“…Both the owl monkey and macaque TRIMCyp gene comparisons have a dS of 0.02 (Fig. 3B), consistent with their birth ∼4.5-6 Mya (16,28). In contrast, the CypA3 comparison between the parental gene and 32myoCypA3 reveals a dS of 0.04 (Fig.…”

“…The phylogeny shows that all four CypA retrogenes split into four distinct monophyletic groups and that the tree topology and branch lengths are consistent with the estimated evolutionary origins of the retrogenes. For instance, the closest outgroup to the CypA retrogenes that gave rise to Aotus TRIMCyp (CypA1) is the Aotus CypA gene, confirming that Aotus CypA1 retrogenes are derived from a CypA gene within the Aotus genus (16). We are unable to gain high resolution within the hominoid and Old World monkey CypA (parental) genes due to the very high identity of these sequences, likely the consequence of extremely strong purifying selection (31).…”

“…Such a gene fusion was first identified in owl monkeys (Aotus trivirgatus), which encode a fusion protein between the TRIM5 gene and a retrotransposed CyclophilinA (CypA1) gene, called the TRIMCyp gene fusion (15). The retrotransposition of CypA between exons 7 and 8 of owl monkey TRIM5 (15) occurred 4.5-6 Mya (16,17). Like TRIM5α, the resulting TRIMCyp protein contains RING, B-box 2, and coiledcoil domains.…”

Chance favors a prepared genome

“…Although we have no way of knowing which retrovirus provided the selective forces in Aotus or Macaca for Trim5CypA1 or Trim5CypA2, selection certainly seems to have occurred, because all 10 species of owl monkey have Trim5CypA1 (20) and members of three of the major groups (15) …”