Retroelements and the human genome: New perspectives on an old relation

Abstract

Retroelements constitute a large portion of our genomes. One class of these elements, the human endogenous retroviruses (HERVs), is comprised of remnants of ancient exogenous retroviruses that have gained access to the germ line. After integration, most proviruses have been the subject of numerous amplifications and have suffered extensive deletions and mutations. Nevertheless, HERV-derived transcripts and proteins have been detected in healthy and diseased human tissues, and HERV-K, the youngest, most conserved family, is able to form virus-like particles. Although it is generally accepted that the integration of retroelements can cause significant harm by disrupting or disregulating essential genes, the role of HERV expression in the etiology of malignancies and autoimmune and neurologic diseases remains controversial. In recent years, striking evidence has accumulated indicating that some proviral sequences and HERV proteins might even serve the needs of the host and are therefore under positive selection. The remarkable progress in the analysis of host genomes has brought to light the significant impact of HERVs and other retroelements on genetic variation, genome evolution, and gene regulation.A lmost half of the mammalian genome is derived from ancient transposable elements. The two general types, (DNA)-transposons and retroelements, often regarded as ''selfish DNA parasites or junk DNA,'' encompass Ϸ2.8% and 42.2% of the human genome, respectively (1, 2). This striking finding is one of the many insights from recent large-scale sequencing projects that have provided the most valuable information in this field since the initial discovery of mobile elements in 1956 by Barbara McClintock (3, 4). Whereas DNA-transposons amplify without an RNA intermediate, retroelements rely on an RNA transcript that is retrotranscribed by a reverse transcriptase before integration in the genome. Here, we briefly review the characteristics of retroelements, their present classification, and the available evidence for their biological significance and function in normal and pathological processes. The focus is on human endogenous retroviruses (HERVs), the remnants of ancient germ-cell infections. Although most of the HERV proviruses have undergone extensive deletions and mutations, some have retained ORFs coding for functional proteins. A few families, including the HERV-K (HML-2) group, have been shown to form viral particles (5, 6), and an apparently intact provirus has recently been discovered in a small fraction of the human population, indicating a very recent acquisition (5-7). Classification of RetroelementsRetroelements constitute 90% of the Ϸ3 million transposable elements present in the human genome (1). They are split into two large groups, the non-LTR and LTR elements (Fig. 1). Two of the non-LTR members are present in extremely high copy numbers in the mammalian germ line: the short interspersed elements (SINE) with the prominent Alu and MIR repeats and the long-terminal interspersed elements (LINE) containing the...

Inhibiting DNA Methylation Causes an Interferon Response in Cancer via dsRNA Including Endogenous Retroviruses

“…The above data suggests Aza might activate endogenous retroviral sequences (ERVs) that constitute more than 8% of the human genome, can activate cytosolic RNA sensors, and are silenced in normal somatic cells by promoter DNA methylation (Bannert and Kurth, 2004) (Tristem, 2000) (Hurst and Magiorkinis, 2014) (Mankan et al, 2014). Some cancers lose ERV DNA methylation and aberrantly overexpress ERVs Cohen et al, 1988;Larsen et al, 2009;Larsson et al, 2007;Rycaj et al, 2014;Strick et al, 2007;Strissel et al, 2012;Wang-Johanning et al, 2001;Wang-Johanning et al, 2007) while others maintain silencing.…”

Transposable elements in the mammalian germline: a comfortable niche or a deadly trap?

“…In the context of somatic cells, cancer can develop, and cases of colorectal cancer have been linked to L1 insertion disrupting the tumor-suppressor gene adenomatous polyposis coli (Miki et al, 1992). A variety of mutant phenotypes caused by TE-induced insertions and rearrangements have also been documented in mouse, and include tumors, infertility and developmental pathologies (Bannert and Kurth, 2004). Independently of their activity, TE toxicity can occur in a retrotransposition-independent manner; overexpression of the L1 ORF2 protein single-handedly induces double-strand breaks and promotes apoptotic and senescence-like responses in cellular assays (Wallace et al, 2008).…”

Mobility and integration sites of a murine C57BL/6 melanoma endogenous retrovirus involved in tumor progression in vivo

“…Interestingly, all mammalian genomes contain endogenous retroviruses (ERVs) that are the genomic traces of ancestral infections of the germline by active retroviruses. [4][5][6] Most of these elements are defective, but some of them have retained intact open reading frames (ORFs). These elements are normally silent but several of them are found to be transcriptionally activated in some tumors, as revealed by the occurrence of viral-like particles.…”