Evolution of the rodent Trim5 cluster is marked by divergent paralogous expansions and independent acquisitions of TrimCyp fusions

Guney Boso,Esther Shaffer,Kathryn Cavanna,Qingping Liu,Alicia Buckler-White,Christine A Kozak

doi:10.1038/s41598-019-47720-5

Guney Boso, Esther Shaffer + Show 4 more

Open Access

PDF Available

https://doi.org/10.1038/s41598-019-47720-5

Copy DOI

Export

Save

Cite

Abstract
Highlights/Summary
Full-Text PDF
Similar Papers

Abstract

Listen

Evolution of cellular innate immune genes in response to viral threats represents a rich area of study for understanding complex events that shape mammalian genomes. One of these genes, TRIM5, is a retroviral restriction factor that mediates a post-entry block to infection. Previous studies on the genomic cluster that contains TRIM5 identified different patterns of gene amplification and the independent birth of CypA gene fusions in various primate species. However, the evolution of Trim5 in the largest order of mammals, Rodentia, remains poorly characterized. Here, we present an expansive phylogenetic and genomic analysis of the Trim5 cluster in rodents. Our findings reveal substantial evolutionary changes including gene amplifications, rearrangements, loss and fusion. We describe the first independent evolution of TrimCyp fusion genes in rodents. We show that the TrimCyp gene found in some Peromyscus species was acquired about 2 million years ago. When ectopically expressed, the P. maniculatus TRIMCyp shows anti-retroviral activity that is reversed by cyclosporine, but it does not activate Nf-κB or AP-1 promoters, unlike the primate TRIMCyps. These results describe a complex pattern of differential gene amplification in the Trim5 cluster of rodents and identify the first functional TrimCyp fusion gene outside of primates and tree shrews.

Highlights

Throughout millions of years of evolutionary history, retroviruses have adapted to living in concert with their hosts
Not long after the initial discovery of TRIM5 as a retroviral restriction factor, it was demonstrated that the restriction of HIV-1 infection in owl monkey cells is caused by the expression of an unusual fusion protein made up of the N-terminal R-B-Coiled Coil (CC) domains of TRIM5 and a cyclophilin A (CypA) domain at the C-terminus[20,21]
Our findings show that the TRIMCyp of P. maniculatus has antiviral activity against HIV-1 in a dose-dependent manner when ectopically expressed, but unlike the primate TRIMCyp fusion genes, it does not activate NF-κB or AP-1 promoters, genes involved in innate immune responses

Summary

Introduction

Throughout millions of years of evolutionary history, retroviruses have adapted to living in concert with their hosts. A few years after this discovery, an independently evolved TRIMCyp fusion gene, with a distinct retroviral restriction capacity was identified in some species of the genus Macaca[22,23,24,25,26] This convergently evolved macaque TRIMCyp results from insertion of a retrotransposed CypA gene downstream of the TRIM5 exon 822–24. Our findings show that the TRIMCyp of P. maniculatus has antiviral activity against HIV-1 in a dose-dependent manner when ectopically expressed, but unlike the primate TRIMCyp fusion genes, it does not activate NF-κB or AP-1 promoters, genes involved in innate immune responses These results document a complex history of genomic remodeling of the rodent Trim[5] cluster and produce evidence of the independent genesis of TrimCyp fusion genes in the order Rodentia, all of which may reflect evolving responses to novel retroviral challenges

Methods

Results

Conclusion