Abstract
All genes in the TRIM6/TRIM34/TRIM5/TRIM22 locus are type I interferon inducible, with TRIM5 and TRIM22 possessing antiviral properties. Evolutionary studies involving the TRIM6/34/5/22 locus have predominantly focused on the coding sequence of the genes, finding that TRIM5 and TRIM22 have undergone high rates of both non-synonymous nucleotide replacements and in-frame insertions and deletions. We sought to understand if divergent evolutionary pressures on TRIM6/34/5/22 coding regions have selected for modifications in the non-coding regions of these genes and explore whether such non-coding changes may influence the biological function of these genes. The transcribed genomic regions, including the introns, of TRIM6, TRIM34, TRIM5, and TRIM22 from ten Haplorhini primates and one prosimian species were analyzed for transposable element content. In Haplorhini species, TRIM5 displayed an exaggerated interspecies variability, predominantly resulting from changes in the composition of transposable elements in the large first and fourth introns. Multiple lineage-specific endogenous retroviral long terminal repeats (LTRs) were identified in the first intron of TRIM5 and TRIM22. In the prosimian genome, we identified a duplication of TRIM5 with a concomitant loss of TRIM22. The transposable element content of the prosimian TRIM5 genes appears to largely represent the shared Haplorhini/prosimian ancestral state for this gene. Furthermore, we demonstrated that one such differentially fixed LTR provides for species-specific transcriptional regulation of TRIM22 in response to p53 activation. Our results identify a previously unrecognized source of species-specific variation in the antiviral TRIM genes, which can lead to alterations in their transcriptional regulation. These observations suggest that there has existed long-term pressure for exaptation of retroviral LTRs in the non-coding regions of these genes. This likely resulted from serial viral challenges and provided a mechanism for rapid alteration of transcriptional regulation. To our knowledge, this represents the first report of persistent evolutionary pressure for the capture of retroviral LTR insertions.
Highlights
The human genome encodes in excess of 70 tripartite motifcontaining (TRIM) genes
Variability in TRIM5, and the genomic locus in which it resides, reflects the consequences of such selective pressures. This is embodied by: the variation in copy number of TRIM5, TRIM22, and TRIM34 between species [5,6,26], elevated rates of non-synonymous change in the coding sequence of TRIM5 and TRIM22 [4,5,45], maintenance of balanced polymorphisms as well as cross-species sharing of polymorphisms in TRIM5 [70,71], and convergent evolution of exon replacement via cDNA retrotransposition [36,72,73,74,75,76,77]
For the four TRIM genes studied here, we found that the degree of nucleotide divergence between species for each gene parallels the dN/dS rate ratio previously reported for the coding regions of that gene [4,61]
Summary
The human genome encodes in excess of 70 tripartite motifcontaining (TRIM) genes. This family of genes is characterized by the presence of a RING domain, one or two B-box domains, and a coiled-coil domain. The C-termini of these genes can consist of one or more of a select number of protein domains, with the majority of the TRIM genes in the human genome containing either a SPRY or PRY-SPRY (B30.2) domain at their C-terminus [1]. A number of B30.2 domain containing TRIM genes have been implicated in host defense mechanisms owing to their transcriptional induction following interferon or viral stimulation [7,9,10] or to their inherent ability to inhibit viral replication [11,12,13]. Primate TRIM6, TRIM34, TRIM22 and TRIM5 are all interferon inducible [9], while TRIM5 and TRIM22 possess antiviral properties [11,12,13]
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