Discordant Evolution of the Adjacent Antiretroviral Genes TRIM22 and TRIM5 in Mammals

Abstract

TRIM5α provides a cytoplasmic block to retroviral infection, and orthologs encoded by some primates are active against HIV. Here, we present an evolutionary comparison of the TRIM5 gene to its closest human paralogs: TRIM22, TRIM34, and TRIM6. We show that TRIM5 and TRIM22 have a dynamic history of gene expansion and loss during the evolution of mammals. The cow genome contains an expanded cluster of TRIM5 genes and no TRIM22 gene, while the dog genome encodes TRIM22 but has lost TRIM5. In contrast, TRIM6 and TRIM34 have been strictly preserved as single gene orthologs in human, dog, and cow. A more focused analysis of primates reveals that, while TRIM6 and TRIM34 have evolved under purifying selection, TRIM22 has evolved under positive selection as was previously observed for TRIM5. Based on TRIM22 sequences obtained from 27 primate genomes, we find that the positive selection of TRIM22 has occurred episodically for approximately 23 million years, perhaps reflecting the changing pathogenic landscape. However, we find that the evolutionary episodes of positive selection that have acted on TRIM5 and TRIM22 are mutually exclusive, with generally only one of these genes being positively selected in any given primate lineage. We interpret this to mean that the positive selection of one gene has constrained the adaptive flexibility of its neighbor, probably due to genetic linkage. Finally, we find a striking congruence in the positions of amino acid residues found to be under positive selection in both TRIM5α and TRIM22, which in both proteins fall predominantly in the β2-β3 surface loop of the B30.2 domain. Astonishingly, this same loop is under positive selection in the multiple cow TRIM5 genes as well, indicating that this small structural loop may be a viral recognition motif spanning a hundred million years of mammalian evolution.

Author Summary

The intrinsic immunity protein TRIM5α provides a post-entry defense against retroviral infection, which depends on its specific ability to recognize retroviral capsids. TRIM5α has been locked in genetic conflict with retroviruses throughout most of primate evolution, characterized by a higher than expected rate of amino acid change, referred to as positive selection. Here, we find that one of TRIM5's closest human paralogs, TRIM22, has also undergone positive selection in primates. However, we find that its close linkage to TRIM5 has resulted in an anti-correlated pattern of positive selection, with primate lineages generally showing positive selection in either TRIM5 or TRIM22, but not both. Amino acid positions in TRIM22 found to be under positive selection are in remarkable proximity to the “antiviral specificity patch” previously described for TRIM5α. TRIM5 and TRIM22 evolution appears to be equally discordant in other mammals; the cow genome contains an expanded cluster of TRIM5 genes and no TRIM22 gene, while the dog genome encodes TRIM22 but has lost TRIM5. Our analyses highlight TRIM22 as bearing all the evolutionary hallmarks of a candidate intrinsic immunity gene.