BackgroundAbout half of the human genome is constituted of transposable elements, including human endogenous retroviruses (HERV). HERV sequences represent the 8% of our genetic material, deriving from exogenous infections occurred millions of years ago in the germ line cells and being inherited by the offspring in a Mendelian fashion. HERV-K elements (classified as HML1–10) are among the most studied HERV groups, especially due to their possible correlation with human diseases. In particular, the HML10 group was reported to be upregulated in persistent HIV-1 infected cells as well as in tumor cells and samples, and proposed to have a role in the control of host genes expression. An individual HERV-K(HML10) member within the major histocompatibility complex C4 gene has even been studied for its possible contribution to type 1 diabetes susceptibility. Following a first characterization of the HML10 group at the genomic level, performed with the innovative software RetroTector, we have characterized in detail the 8 previously identified HML10 sequences present in the human genome, and an additional HML10 partial provirus in chromosome 1p22.2 that is reported here for the first time.ResultsUsing a combined approach based on RetroTector software and a traditional Genome Browser Blat search, we identified a novel HERV-K(HML10) sequence in addition to the eight previously reported in the human genome GRCh37/hg19 assembly. We fully characterized the nine HML10 sequences at the genomic level, including their classification in two types based on both structural and phylogenetic characteristics, a detailed analysis of each HML10 nucleotide sequence, the first description of the presence of an Env Rec domain in the type II HML10, the estimated time of integration of individual members and the comparative map of the HML10 proviruses in non-human primates.ConclusionsWe performed an unambiguous and exhaustive analysis of the nine HML10 sequences present in GRCh37/hg19 assembly, useful to increase the knowledge of the group’s contribution to the human genome and laying the foundation for a better understanding of the potential physiological effects and the tentative correlation of these sequences with human pathogenesis.Electronic supplementary materialThe online version of this article (10.1186/s13100-017-0099-7) contains supplementary material, which is available to authorized users.
Eight percent of the human genome is composed of human endogenous retroviruses (HERVs), remnants of ancestral germ line infections by exogenous retroviruses, which have been vertically transmitted as Mendelian characters. The HML-6 group, a member of the class II betaretrovirus-like viruses, includes several proviral loci with an increased transcriptional activity in cancer and at least two elements that are known for retaining an intact open reading frame and for encoding small proteins such as ERVK3-1, which is expressed in various healthy tissues, and HERV-K-MEL, a small Env peptide expressed in samples of cutaneous and ocular melanoma but not in normal tissues. IMPORTANCE We reported the distribution and genetic composition of 66 HML-6 elements. We analyzed the phylogeny of the HML-6 sequences and identified two main clusters. We provided the first description of a Rec domain within the env sequence of 23 HML-6 elements. A Rec domain was also predicted within the ERVK3-1 transcript sequence, revealing its expression in various healthy tissues. Evidence about the context of insertion and colocalization of 19 HML-6 elements with functional human genes are also reported, including the sequence 16p11.2, whose 5= long terminal repeat overlapped the exon of one transcript variant of a cellular zinc finger upregulated and involved in hepatocellular carcinoma. The present work provides the first complete overview of the HML-6 elements in GRCh37(hg19), describing the structure, phylogeny, and genomic context of insertion of each locus. This information allows a better understanding of the genetics of one of the most expressed HERV groups in the human genome.A bout 8% of the human genome consists of human endogenous retroviruses (HERVs) (1), resulted from the occasional integration of exogenous retroviruses into the human germ line, which occurred mostly more than 30 million years ago. These proviruses were vertically transmitted to the offspring and then fixed in the genome of the population during the evolution (2, 3), accumulating, over time, several mutations that in most cases compromised their coding capability.Nevertheless, some important examples of HERV involvement in human biology have been demonstrated (2,(4)(5)(6), such as the retroviral protein Syncytin-1, a functional envelope (Env) protein coded by an HERV-W provirus that is involved in trophoblasticcell fusion during pregnancy (7,8). However, in the majority of studies, only general HERV groups and not individual HERV loci have been investigated in detail for their correlation to diseases (9), especially due to the lack, until recently, of any information Citation Pisano MP, Grandi N, Cadeddu M, Blomberg J, Tramontano E. 2019. Comprehensive characterization of the human endogenous retrovirus HERV-K(HML-6) group: overview of structure, phylogeny, and contribution to the human genome. J Virol
We studied several in vitro activities of tumor-associated lympho-monocytes (TALMs) and the concentrations of interleukin (IL)-1a, IL-1b, IL-2, IL-4, IL-6, IL-10, tumor necrosis factor (TNF)a, interferon (IFN)g and soluble IL-2 receptor (sIL-2R) in neoplastic effusions and in the serum of advanced stage cancer patients. Comparisons were made with autologous peripheral blood mononuclear cells (PBMCs). Autologous PBMCs were compared with PBMCs from normal subjects used as controls. TALMs were collected from 13 peritoneal and 18 pleural neoplastic effusions, secondary to primary tumors of different sites. After PHA stimulation, concentrations of IL-1a, IL-1b and TNFa in culture media of TALMs both from peritoneal and pleural effusions were lower than those of autologous PBMCs and, similarly, concentrations of IL-4 and IL-10 in culture media of TALMs from peritoneal effusions were lower than those of autologous PBMCs, whereas concentrations of IL-4 and IL-10 in culture media of TALMs from pleural effusions were in the same range as those of autologous PBMCs. On the contrary, IL-2, IL-6 and IFNg amounts (only from pleural effusions) were significantly higher. IL-1a, IL-1b, IL-2, IL-6 and TNFa production from patient PBMCs was lower than that of control PBMCs, whereas production of IL-4, IL-10 and IFNg was higher than that of control PBMCs. Both in peritoneal and in pleural effusions concentrations of IL-1a, IL-1b and IL-4 were not different from those measured in autologous serum, whereas those of IL-6, IL-10, TNFa, IFNg and sIL-2R were significantly higher. The amounts of IL-2 in pleural effusions were not different from those of autologous serum, but in peritoneal effusions they were higher than those of autologous serum. The amounts of IL-1a, IL-1b, IL-2, IL-6, TNFa and sIL-2R were higher in patient than in control sera, whereas those of IL-4, IL-10 and IFNg were in the same range in patient and in control sera. Cell cycle analysis of cultured TALMs and PBMCs (from 3 patients) showed a significant accumulation of TALMs in the non-cycling G 0 /G 1 cell population compared with autologous PBMCs. Int.
Endogenous Retroviruses (ERVs) are ancient relics of infections that affected the primate germ line and constitute about 8% of our genome. Growing evidence indicates that ERVs had a major role in vertebrate evolution, being occasionally domesticated by the host physiology. In addition, human ERV (HERV) expression is highly investigated for a possible pathological role, even if no clear associations have been reported yet. In fact, on the one side, the study of HERV expression in high-throughput data is a powerful and promising tool to assess their actual dysregulation in diseased conditions; but, on the other side, the poor knowledge about the various HERV group genomic diversity and individual members somehow prevented the association between specific HERV loci and a given molecular mechanism of pathogenesis. The present study is focused on the HERV-K(HML7) group that—differently from the other HERV-K members—still remains poorly characterized. Starting from an initial identification performed with the software RetroTector, we collected 23 HML7 proviral insertions and about 160 HML7 solitary LTRs that were analyzed in terms of genomic distribution, revealing a significant enrichment in chromosome X and the frequent localization within human gene introns as well as in pericentromeric and centromeric regions. Phylogenetic analyses showed that HML7 members form a monophyletic group, which based on age estimation and comparative localization in non-human primates had its major diffusion between 20 and 30 million years ago. Structural characterization revealed that besides 3 complete HML7 proviruses, the other group members shared a highly defective structure that, however, still presents recognizable functional domains, making it worth further investigation in the human population to assess the presence of residual coding potential.
Glucose-6-phosphate dehydrogenase (G6PD) and 6-phosphogluconate, dehydrogenase the key enzymes of the hexose monophosphate shunt pathway, were measured in both surrounding and tumoral lung tissues from normal and G6PD-deficient subjects. A significant increase of these enzymatic activities in tumoral tissue was found not only in G6PD-normal patients, but also in G6PD-deficient patients with very low or nonmeasurable G6PD activity in both erythrocytes and normal lung tissue.
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