Abstract

   Systemic lupus erythematosus (SLE) is a chronic autoimmune disease
   characterized by the production of autoantibodies predominantly to
   nuclear material. Many aspects of disease pathology are mediated by the
   deposition of nucleic acid containing immune complexes, which also
   induce the type 1interferon response, a characteristic feature of SLE.
   Notably, SLE is remarkably heterogeneous, with a variety of organs
   involved in different individuals, who also show variation in disease
   severity related to their ancestries. Here, we probed one potential
   contribution to disease heterogeneity as well as a possible source of
   immunoreactive nucleic acids by exploring the expression of human
   endogenous retroviruses (HERVs). We investigated the expression of
   HERVs in SLE and their potential relationship to SLE features and the
   expression of biochemical pathways, including the interferon gene
   signature (IGS). Towards this goal, we analyzed available and new
   RNA-Seq data from two independent whole blood studies using Telescope.
   We identified 481 locus specific HERV encoding regions that are
   differentially expressed between case and control individuals with only
   14% overlap of differentially expressed HERVs between these two
   datasets. We identified significant differences between differentially
   expressed HERVs and non-differentially expressed HERVs between the two
   datasets. We also characterized the host differentially expressed genes
   and tested their association with the differentially expressed HERVs.
   We found that differentially expressed HERVs were significantly more
   physically proximal to host differentially expressed genes than
   non-differentially expressed HERVs. Finally, we capitalized on locus
   specific resolution of HERV mapping to identify key molecular pathways
   impacted by differential HERV expression in people with SLE.

   Keywords: HERV human endogenous retroviruses, lupus (SLE), RNA-Seq,
   deep learning - artificial neural network (DL-ANN), retrovirus < virus
   classification

Introduction

   Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease
   with the primary demographic affected being women of childbearing ages
   ([43]1). At least 70% of lupus cases are systemic ([44]2). SLE is
   characterized by dysregulation of both the innate and adaptive immune
   systems, resulting in the production of pathogenic autoantibodies and
   increased activity of the type I interferon system. Whereas a number of
   genetic regions have been identified as associated with risk for lupus
   ([45]3, [46]4), host genetics alone has failed to fully explain the
   disease, suggesting an important role for environmental
   stimuli. Exogenous stimuli, such as ultraviolet light and cigarette
   smoking have been implicated in SLE pathogenesis. Recent work has
   suggested that endogenous elements, including transposable elements
   ([47]5) and human endogenous retroviruses (HERVs) ([48]6) may also play
   a pathogenic role in SLE.

   HERVs make up between 5-8% of the human genome and are a subset of
   transposable genomic elements ([49]7). HERVs are structurally similar
   to infectious retroviruses and contain gag, pol, and env genes in their
   genomes. These genes code for core viral proteins, reverse
   transcriptase, and envelope proteins, respectively. Their integration
   site preferences on chromosomes can vary widely as well ([50]8).