Positive selection of the TRIM family regulatory region in primate genomes

Abstract

Viral selection pressure has acted on restriction factors that play an important role in the innate immune system by inhibiting the replication of viruses during primate evolution. Tripartite motif-containing (TRIM) family members are some of these restriction factors. It is becoming increasingly clear that gene expression differences, rather than protein-coding regions changes, could play a vital role in the anti-retroviral immune mechanism. Increasingly, recent studies have created genome-scale catalogues of DNase I hypersensitive sites (DHSs), which demark potentially functional regulatory DNA. To improve our understanding of the molecular evolution mechanism of antiviral differences between species, we leveraged 14 130 DHSs derived from 145 cell types to characterize the regulatory landscape of the TRIM region. Subsequently, we compared the alignments of the DHSs across six primates and found 375 DHSs that are conserved in non-human primates but exhibit significantly accelerated rates of evolution in the human lineage (haDHSs). Furthermore, we discovered 31 human-specific potential transcription factor motifs within haDHSs, including the KROX and SP1, that both interact with HIV-1. Importantly, the corresponding haDHS was correlated with antiviral factor TRIM23. Thus, our results suggested that some viruses may contribute, through regulatory DNA differences, to organismal evolution by mediating TRIM gene expression to escape immune surveillance.

Genetic contributions to lupus nephritis in a multi-ethnic cohort of systemic lupus erythematous patients

“…This is suggestive of linking a potential variant influencing the function of at least TRIM15, which would have an effect on the ability to restrict endogenous retro-elements from inducing an IFN response. If confirmed in independent datasets, additional work will be required to understand why these genes are associated with LN only among South Europeans, although differences in selection pressures in different geographic regions might explain such differences [ 27 ]. Due to the nature of the gene-based analysis, we do not have the direction of the association (protective or risk), but we know that Europeans are protected from LN in comparison to other populations [ 4 ].…”

The TRIMendous Role of TRIMs in Virus–Host Interactions

“…The close proximity of several TRIMs, particularly those with a B30.2 domain, near known immune genes such as HLA (Human Leukocyte Antigen) [ 38 , 39 , 40 ] supports immune regulation as a TRIM-mediated function. Additionally, the regulatory regions of several TRIMs include target sequences recognized by transcription factors involved in coordinating immune responses [ 42 ]. The species-specific expansion of B30.2-containing TRIMs [ 32 , 43 ] suggests that this group is specialized.…”

“…Additionally, the region encoding the C-terminus of many TRIMs is under positive selection [ 32 , 39 , 41 , 43 , 44 ]. The non-coding, transcriptional regulatory regions of more recently evolved TRIM genes are also under positive selection [ 42 ]. This species-specific pattern of positive selection of closely related TRIMs suggests that individual TRIMs play specific antiviral roles.…”

Cell-Autonomous Immunity and The Pathogen-Mediated Evolution of Humans: Or How Our Prokaryotic and Single-Celled Origins Affect The Human Evolutionary Story

“…There appear to be functional ramifications to these genetic changes. For example, TRIM5a also exhibits species-specific ability to recognize and degrade viral capsids, while alterations in transcription factor-binding sites associated with TRIM23 in humans suggests this gene modulates antiviral signaling differently in our species than in other primates (Sawyer et al 2005;Ortiz et al 2009;Nakayama and Shioda 2012;He et al 2016). Such rapid evolution has been traditionally credited to conflict with ancient viruses, and has been noted in APOBEC genes as well.…”