HERV-K(HML7) Integrations in the Human Genome: Comprehensive Characterization and Comparative Analysis in Non-Human Primates

SIMPLE SUMMARY: The human genome is not human at all, but it includes a multitude of sequences inherited from ancient viral infections that affected primates’ germ line. These elements can be seen as the fossils of now-extinct retroviruses, and are called Human Endogenous Retroviruses (HERVs). View as “junk DNA” for a long time, HERVs constitute 4 times the amount of DNA needed to produce all cellular proteins, and growing evidence indicates their crucial role in primate brain evolution, placenta development, and innate immunity shaping. HERVs are also intensively studied for a pathological role, even if the incomplete knowledge about their exact number and genomic position has thus far prevented any causal association. Among possible relevant HERVs, the HERV-K supergroup is of particular interest, including some of the oldest (HML5) as well as youngest (HML2) integrations. Among HERV-Ks, the HML7 group still lack a detailed description, and the present work thus aimed to identify and characterize all HML7 elements in the human genome. Results showed that the HML7 group includes 23 elements and an additional 160 “scars” of past infection that invaded in primates mostly between 20 and 30 million years ago, providing an exhaustive background to study their impact on human pathophysiology. ABSTRACT: Endogenous Retroviruses (ERVs) are ancient relics of infections that affected the primate germ line and constitute about 8% of our genome. Growing evidence indicates that ERVs had a major role in vertebrate evolution, being occasionally domesticated by the host physiology. In addition, human ERV (HERV) expression is highly investigated for a possible pathological role, even if no clear associations have been reported yet. In fact, on the one side, the study of HERV expression in high-throughput data is a powerful and promising tool to assess their actual dysregulation in diseased conditions; but, on the other side, the poor knowledge about the various HERV group genomic diversity and individual members somehow prevented the association between specific HERV loci and a given molecular mechanism of pathogenesis. The present study is focused on the HERV-K(HML7) group that—differently from the other HERV-K members—still remains poorly characterized. Starting from an initial identification performed with the software RetroTector, we collected 23 HML7 proviral insertions and about 160 HML7 solitary LTRs that were analyzed in terms of genomic distribution, revealing a significant enrichment in chromosome X and the frequent localization within human gene introns as well as in pericentromeric and centromeric regions. Phylogenetic analyses showed that HML7 members form a monophyletic group, which based on age estimation and comparative localization in non-human primates had its major diffusion between 20 and 30 million years ago. Structural characterization revealed that besides 3 complete HML7 proviruses, the other group members shared a highly defective structure that, however, still presents recognizable functional domains, making it worth further investigation in the human population to assess the presence of residual coding potential.