Human Endogenous Retrovirus-K (HML-2)-Related Genetic Variation: Human Genome Diversity and Disease

Abstract

Human endogenous retroviruses (HERVs) comprise a significant portion of the human genome, making up roughly 8%, a notable comparison to the 2-3% represented by coding sequences. Numerous studies have underscored the critical role and importance of HERVs, highlighting their diverse and extensive influence on the evolution of the human genome and establishing their complex correlation with various diseases. Among HERVs, the HERV-K (HML-2) subfamily has recently attracted significant attention, integrating into the human genome after the divergence between humans and chimpanzees. Its insertion in the human genome has received considerable attention due to its structural and functional characteristics and the time of insertion. Originating from ancient exogenous retroviruses, these elements succeeded in infecting germ cells, enabling vertical transmission and existing as proviruses within the genome. Remarkably, these sequences have retained the capacity to form complete viral sequences, exhibiting activity in transcription and translation. The HERV-K (HML-2) subfamily is the subject of active debate about its potential positive or negative effects on human genome evolution and various pathologies. This review summarizes the variation, regulation, and diseases in human genome evolution arising from the influence of HERV-K (HML-2).

Keywords: HERV-K; HML-2; diseases; genetic variation; genome diversity; human endogenous retrovirus-K.

Figure 1

Typical structure and potential functions of HERV-K (HML-2) in the human genome. (a) General structure of HERV-K (HML-2). The typical full-length HERV-K (HML-2) is approximately 9.5 kb and is flanked by two long terminal repeats (LTRs). A typical HERV-K (HML-2) insertion forms a target site duplication (red box) by its insertion mechanism. The internal sequence has virus-like open reading frames (ORFs), largely composed of the gag, pro, pol, and env genes. This element can exist in two types (type I and II), with type I being a deletion of 292 bp at the border of the pol and env genes. (b) The LTRs exist as solitary LTRs through various genomic events within the human genome. Promoters, polyadenylation signals, enhancer cores, and putative factor-binding sites are present within LTRs and thus have the potential to play an important role in gene expression regulation and genomic variation. (c) HERV-K (HML-2) provides a splicing donor 3 (SD3) due to a 292 bp deletion at the border of the pol and env genes. As a result, type II expresses transcripts for the Env and Rec proteins and type I expresses transcripts that can produce the Np9 protein. (d) The LTRs after HERV-K (HML-2) insertion have very high sequence similarity; thus, homologous recombination can result in a duplicated form with two HERV-K internal regions and three LTRs, or it can exist as a solitary LTR. (e) Schematic of the non-classical insertion of HERV-K (HML-2) in the human genome. When double-strand breaks (DBSs) occur in ancient genomes, some existing sequences are deleted and truncated HML-2 sequences are inserted into the human genome without TSDs through microhomologies. (f) HERV-K (HML-2) drives changes in the human genome not only through its internal sequence, but also through its LTRs. LTRs have various regulatory elements within them and affect the human genome through antisense promoters, promoters, enhancers, polyadenylation signals, etc. They provide splicing donors and acceptors through their insertions. They also directly alter gene expressions through epigenetic changes. (g) HERV-K (HML-2) still show activity and due to their structural features, the specific insertion site exists in various forms within the diploid human genome. This means that they are still contributing to inter-individual genomic polymorphisms. (h) These elements are among the retrotransposons that were recently inserted into the human genome, so they have a very high degree of sequence similarity. These sequences can potentially cause genomic variation through interchromosomal recombination or intrachromosomal recombination.

Figure 2

Diagram of HERV-K (HML-2) and its relationship to disease. The proteins expressed by this element, Gag, Pro, Env, Rec, and Np9, interact with various host genes to induce abnormal cellular physiological responses. The black arrows indicate their respective associations. These proteins are known to affect human diseases, including various malignancies, by influencing inflammatory responses, the immune system, and cell growth and progression.