Evolution of TRIM5 and TRIM22 in Bats Reveals a Complex Duplication Process

Abstract

The innate immunological response in mammals involves a diverse and complex network of many proteins. Over the last years, the tripartite motif-containing protein 5 (TRIM5) and 22 (TRIM22) have shown promise as restriction factors of a plethora of viruses that infect primates. Although there have been studies describing the evolution of these proteins in a wide range of mammals, no prior studies of the TRIM6/34/5/22 gene cluster have been performed in the Chiroptera order. Here, we provide a detailed analysis of the evolution of this gene cluster in several bat genomes. Examination of different yangochiroptera and yinpterochiroptera bat species revealed a dynamic history of gene expansion occurring in TRIM5 and TRIM22 genes. Multiple copies of TRIM5 were found in the genomes of several bats, demonstrating a very low degree of conservation in the synteny of this gene among species of the Chiroptera order. Our findings also reveal that TRIM22 is often found duplicated in yangochiroptera bat species, an evolutionary phenomenon not yet observed in any other lineages of mammals. In total, we identified 31 TRIM5 and 19 TRIM22 amino acids to be evolving under positive selection, with most of the residues being placed in the PRYSPRY domain, known to be responsible for binding to the viral capsid during restriction in the primate orthologous TRIM proteins. Altogether, our results help to shed light on the distinctive role of bats in nature as reservoirs of viruses, many of which have become threatening zoonotic diseases through virus spillover in the last decades.

Adaptive duplication and functional diversification of Protein kinase R contribute to the uniqueness of bat-virus interactions

“…Here, the adaptive changes in bat PKRs increase the antiviral function and the viral evasion of PKR, which supports an adaptive enhancement for viral control in some species. This is in line with several studies reporting accelerated rate of evolution in bat restriction factors, indicating increased defense against virus infection 13,17,50,69 . Since each species has its own history of viral exposure, specific viral communities have certainly led to lineage-specific selection in bat’s antiviral immunity, highlighting the need to include multiple related species in comparative functional studies.…”

“…While all other studied mammals possess one single gene encoding PKR, several bat species from the Myotis genus express at least two functional, genetically divergent copies of PKR. Expansions of genes encoding antiviral proteins were previously discovered in bat species, including the APOBEC3, TRIM 22/5 and IFITM3 gene families, as well as the chimeric protein HERC5/6, or BST2 14,16,17,45,50 .…”

“…While all other studied mammals possess one single gene encoding PKR, several bat species from the Myotis genus express at least two functional, genetically divergent copies of PKR. Expansions of genes encoding antiviral proteins were previously discovered in bat species, including the APOBEC3, TRIM 22/5 and IFITM3 gene families, as well as the chimeric protein HERC5/6, or BST2 14,16,17,45,50 . Importantly, however, these duplications involve known multigene immune families, which are prone to gene expansion in many mammals, in contrast to the EIF2AK2 (PKR) locus that is highly conserved in other mammals.…”

“…As a result, specific adaptive changes may also enable bats to efficiently control viral infections 12 . For example, a handful of bat antiviral factors bear signatures of strong positive selection and gene duplications 12,13 , including key restriction factors, such as APOBECs 12,14 , MX family GTPases 15 , IFITM3 16 and TRIM5/22 17 . Nevertheless, efforts to broadly and comprehensively characterize the functional diversification of bat restriction factors, compared to other functional approach, we show that long-standing genetic conflicts with viral pathogens have driven the rapid evolution and duplication of bat PKRs, and the resulting adaptive changes account for modern host-virus antagonism specificity.…”

Adaptive duplication and genetic diversification of protein kinase R contribute to the specificity of bat-virus interactions

“…As a result, specific adaptive changes may also enable bats to efficiently control viral infections ( 9 ). For example, a handful of bat antiviral factors bear signatures of strong positive selection and gene duplications ( 9 ), including key restriction factors, such as Apolipoprotéins B mRNA editing enzyme, catalytic polypeptide-like proteins (APOBECs) ( 9 ), MX family guanosine triphosphatases ( 10 ), interferon-induced transmembrane protein 3 (IFITM3) ( 11 ), and Tripartite Motif Containing 5 and 22 (TRIM5, TRIM22) ( 12 ). Nevertheless, efforts to broadly and comprehensively characterize the functional diversification of bat restriction factors, compared to other mammals, remain very limited.…”