Molecular functions of human endogenous retroviruses in health and disease

Abstract

Human endogenous retroviruses (HERVs) and related genetic elements form 504 distinct families and occupy ~8% of human genome. Recent success of high-throughput experimental technologies facilitated understanding functional impact of HERVs for molecular machinery of human cells. HERVs encode active retroviral proteins, which may exert important physiological functions in the body, but also may be involved in the progression of cancer and numerous human autoimmune, neurological and infectious diseases. The spectrum of related malignancies includes, but not limits to, multiple sclerosis, psoriasis, lupus, schizophrenia, multiple cancer types and HIV. In addition, HERVs regulate expression of the neighboring host genes and modify genomic regulatory landscape, e.g., by providing regulatory modules like transcription factor binding sites (TFBS). Indeed, recent bioinformatic profiling identified ~110,000 regulatory active HERV elements, which formed at least ~320,000 human TFBS. These and other peculiarities of HERVs might have played an important role in human evolution and speciation. In this paper, we focus on the current progress in understanding of normal and pathological molecular niches of HERVs, on their implications in human evolution, normal physiology and disease. We also review the available databases dealing with various aspects of HERV genetics.

Keywords: Autoimmune disorders; Cancer; Genome evolution; Human endogenous retrovirus; Infectious diseases; Long terminal repeat.

Fig. 1

Functional genes encoded by HERVs, on the example of HERV-K (HML-2) elements. a Genomic organization of the reconstituted full-size provirus. Apart from “classical” retroviral genes Gag, Prot, Pol and Env, an additional gene Rec or Np9, depending on the provirus type, is encoded. b Different types of proviral transcripts. Full-length subgenomic transcript encodes for Gag–Prot–Pol polyprotein, single-spliced product codes Envelope protein, double-spliced RNA is for Rec/Np9, whereas ~1.5 kb long completely spliced transcript of unknown function appears to lack any functional open reading frames

Fig. 2

Functional roles played by HERV elements (defined as LTRs) in the regulation of gene expression. 1 HERVs may serve as transcriptional enhancers or silencers by regulating activities of downstream promoters. 2 HERVs may act as transcriptional promoters for host non-repetitive DNA, thus creating new genes. 3 HERV polyadenylation sites may cause premature termination of transcription of the host genes. 4 HERV sequences may disrupt exon–intron structure of genes by donating new splice sites. 5 HERVs may initiate antisense transcripts overlapping with RNAs of the host genes