Identification and characterization of Type W Human Endogenous Retroviruses (HERV-W) in humans and comparative analysis of the group in non-human primates: new insights on HERV-W diffusion in Simiiformes and analysis of evolutionarily highly related sequences in New World Monkeys

Human Endogenous Retroviruses (HERVs) are ancient infections relics constituting~8% of our DNA. While HERVs genomic characterization is still ongoing, impressive amounts of data have been obtained on some HERV groups general expression across human tissues, primarily to find a role in pathogenesis. Among HERV groups, one of the most explored is the HERV-W one, initially studied for an element integrated in locus 7q21.2 and encoding a functional envelope protein coopted for placentation. The group has been also highly investigated for its role in several diseases, such as cancer, inflammation and autoimmunity. However, no conclusive correlations have been demonstrated so far. In general, both i) the absence of an exhaustive characterization of the HERV-W group at the genomic level and ii) the lack of a proper identification of which specific HERV-W locus is expressed in a given condition, currently prevents the assessment of the single HERV-W loci expression in the different physio-pathological contexts and their effective exploitation either as innovative diagnostic or therapeutic targets. The present work was aimed to provide a comprehensive characterization of the HERV-W group in the human genome, setting the bases for a more rationale analysis of its specific contribution to our transcriptome to understand the potential effects exerted by HERV-W loci and expressed products. 213 HERV-W sequences were retrieved from human genome assembly GRCh37/hg19 and analyzed in terms of structure, context of insertion, phylogeny and time of integration; providing, to our knowledge, the most complete and exhaustive HERV-W dataset up to date. Moreover, to better understand the dynamics of diffusion of (H)ERV-W elements, we comparatively analyzed the group presence in the genome of 12 non-human primates, belonging to Siimiformes (Catarrhines and Platyrrhines), Tarsiiformes and Prosimians. The data obtained provide a complete analysis of the ERV-W group presence in the primate lineages, including ERV-W loci orthologous to human integrations, ERV-W species-specific insertions and LTR-LTR recombination events along primates speciation, further detailing the group diffusion in primates. Interestingly, in Platyrrhini species we identified an ERV group named ERV1-1 showing high identity to the ERV-W elements. The analysis of the 130 most complete ERV1-1 sequences retrieved from Marmoset (C. jacchus) and Squirrel Monkey (S. boliviensis) allowed us to confirm the phylogenetic relation of the ERV1-1 group to the ERV-W one, possibly suggesting the presence of a common ancestor. To gain more insights into the ERV1-1 group and its unreported relation with ERV-W, the ERV1-1 sequences structure, context of insertion, phylogeny and time of integration have been characterized. Such analysis provided, for the first time, a detailed description of the group, pointing out the various structural features shared with ERV-W elements, among which an unusual “pre gag“ region. Considering that the pre gag is a stable component of the ERV-W structure, for which neither origin nor function has been hypothesized yet, we analyzed in detail this region comparing it with the ERV1-1 pre gag. Results showed that ERV-W and ERV1-1 pre gag share nucleotide identity in the 5’-portion, while~40% of the ERV-W pre gag sequence was highly similar to a portion of the HERVIP10F ORF2, encoding for a pol protein Ribonuclease H domain. The same HERVIP10F-like pre gag region had been provided by the ERV-W sequences to Harlequin mosaic elements, possibly suggesting recombination events involving this portion. Interestingly, in both ERV-W and ERV1-1 consensus sequences, RetroTector software detected the presence of a putative exon spanning the pre gag region. Considering that the predicted encoded peptides showed no homology with any known proteins, further studies are needed to assess the native role of the pre gag elements maintained in these and the other related Gammaretroviruses