Heir persistence in the human genome, it has been proposed that
Heir persistence in the human genome, it has been proposed that HERVs could be neutral sequences, thus not negatively selected and removed during Biotin-VAD-FMK supplement evolution (parasitic theory), or, conversely, they could be involved in important cellular functions leading to their positive selection over time (symbiotic theory) [10]. However, the former theory does not exclude the latter, being possible that, after the initial acquisition, the random accumulation of mutations by the viral DNA could led to the synthesis of divergent proteins that acquired a role for the host, enabling HERVs symbiotic persistence in our DNA PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/28192408 [10, 11]. HERVs are currently divided into three main classes according to their similarity to exogenous elements: I (Gammaretrovirus- and Epsilonretrovirus-like), II (Betaretrovirus-like) and III (Spumaretrovirus-like). The further classification of HERV groups is currently based mainly on pol gene phylogeny, even if the taxonomy has been for a long time based on discordant criteria, such as the human tRNA complementary to the Primer Binding Site (PBS) of each group [12]. In this way, individual HERV groups have been identified based on the amino acid associated to the tRNA putatively priming the reverse transcription, i.e. tryptophan (W) for HERV-W sequences and lysine (K) for HERV-K supergroup. Among class II elements, the HERV-K sequences were originally identified due to their similarity to the Mouse Mammary Tumor Virus (MMTV, Betaretroviruses) [13], and are in fact classified accordingly in 10 so-called human MMTV-like clades (HML1?0) [3]. The HERV-K elements are currently highly investigated due to their possible association with human diseases, especially regarding cancer and autoimmunity. One of the most interesting HERV-K clade is the HML10 one, initially PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/27689333 identified due to a full-lengthprovirus integrated in anti-sense orientation within the ninth intron of the fourth component of human complement gene (C4A) in the class III region of the major histocompatibility complex (MHC) on chromosome 6 short arm [14]. This HML10 provirus was subsequently named HERV-K(C4), and showed a typical retroviral structure with 5- and 3’Long Terminal Repeats (LTR) flanking gag, pol and env genes. The human C4 gene is part of the so-called RCCX cassette, a genetic module composed by four genes: STK19 (serine/threonine nuclear protein kinase), C4 (either in an acid C4A form or a basic C4B form), CYP21 (steroid 21-hydroxylase) and TXN (tenascin) [15]. Remarkably, CYP21A2 contains a recombination site leading to the presence, in the human population, of polymorphic monomodular (69 ), bimodular (17 ) and trimodular (14 ) RCCX cassettes, containing one, two, and three C4 functional copies, respectively [16]. Interestingly, HERV-K(C4) presence or absence determines a dichotomous C4 gene size polymorphism, showing a long (22,5 kb) or a short (16 kb) form, respectively [14, 17, 18]. About three quarters of C4 genes belong to the long variant, including the HERV-K(C4) integration that could be present in 1 to 3 copies according to the C4 harboring gene copy number. For European-diploid genome, the most common C4 copy number is of four copies: two C4A and two C4B [16]. Subsequently, in the human genome assembly reference sequence, HERV-K(C4) provirus is present in two copies, one inserted in C4A and one in C4B, thought to be evolved from a C4 duplication event in a non-human primate ancestor [15] and leading to the presence of two identical proviral inserti.