Characterization of ERV9 Elements within the Human Genome

Human Endogenous Retroviruses (HERVs) are the genomic remains of ancient retroviruses that infected vertebrate genomes millions of years ago. Over evolutionary time, these proviruses have lost their infectious capacity due to an accumulation of mutations in the coding regions and long terminal repeats (LTRs), and most are believed to be transcriptionally silent in normal human tissue. However, recent evidence has shown several mechanisms by which HERV expression can influence homeostatic processes, including alternative enhancers for protein coding genes, activation of non-coding genomic regions, and expression of retroviral transcripts or proteins. The HERV9 family of endogenous retroviruses is of particular interest because it represents one of the more recent endogenization events, and is thus expected to retain more of its functional capacity than older HERV families. Despite this relatively young evolutionary age, HERV9 has been given relatively little attention compared to other HERV families such as HERV-W and HERV-K (HML-2). Finally, HERV9 and its long terminal repeat, LTR12, has been shown to regulate the activity of certain proapoptotic genes involved in prevention of cancer, specifically TP63 and TNFRSF10B in testicular cancer. In the present work, we identified and detailed the location and genomic context of 190 HERV9 elements in humans. This bioinformatic analysis has led to a characterization of all near-complete HERV9 elements in the human reference genome (hg38), with a report on the genomic and epigenomic context of their insertions throughout the genome and a phylogenetic classification of HERV9 subfamilies. Our exploratory analyses show dynamic connectivities within the HERV9 families. This body of work illustrates the importance of HERV9 elements and possible contributions to human homeostasis and pathogenesis. The goal of our study is to provide an exhaustive reference library for HERV9 to be used in understanding its role in both pathology and cooption throughout human evolution