Sequences homologous to human herpesvirus 6 (HHV-6) are integrated within the nuclear genome of about 1% of humans, but it is not clear how this came about. It is also uncertain whether integrated HHV-6 can reactive into an infectious virus. HHV-6 integrates into telomeres, and this has recently been associated with polymorphisms affecting MOV10L1. MOV10L1 is located on the subtelomere of chromosome 22q (chr22q) and is required to make PIWI-interacting RNAs (piRNAs). As piRNAs block germline integration of transposons, piRNA-mediated repression of HHV-6 integration has been proposed to explain this association. In vitro, recombination of the HHV-6 genome along its terminal direct repeats (DRs) leads to excision from the telomere and viral reactivation, but the expected “solo-DR scar” has not been described in vivo. Here we screened for integrated HHV-6 in 7,485 Japanese subjects using whole-genome sequencing (WGS). Integrated HHV-6 was associated with polymorphisms on chr22q. However, in contrast to prior work, we find that the reported MOV10L1 polymorphism is physically linked to an ancient endogenous HHV-6A variant integrated into the telomere of chr22q in East Asians. Unexpectedly, an HHV-6B variant has also endogenized in chr22q; two endogenous HHV-6 variants at this locus thus account for 72% of all integrated HHV-6 in Japan. We also report human genomes carrying only one portion of the HHV-6B genome, a solo-DR, supporting in vivo excision and possible viral reactivation. Together these results explain the recently-reported association between integrated HHV-6 and MOV10L1/piRNAs, suggest potential exaptation of HHV-6 in its coevolution with human chr22q, and clarify the evolution and risk of reactivation of the only intact (non-retro)viral genome known to be present in human germlines.

与人类疱疹病毒6（HHV-6）同源的序列已整合到约1％的人类的核基因组中，但尚不清楚这是如何产生的。还不能确定整合的HHV-6是否可以反应成传染性病毒。HHV-6整合到端粒中，最近这与影响MOV10L1的多态性有关。MOV10L1位于染色体22q（chr22q）的亚端粒上，是制作PIWI相互作用RNA（piRNA）所必需的。由于piRNA阻断转座子的种系整合，因此有人提出了piRNA介导的HHV-6整合抑制。体外然而，HHV-6基因组沿其末端直接重复序列（DR）的重组导致从端粒切除和病毒再活化，但是预期的“ solo-DR疤痕”尚未在体内描述。在这里，我们使用全基因组测序（WGS）在7,485名日本受试者中筛选了整合的HHV-6。整合的HHV-6与chr22q的多态性有关。但是，与先前的工作相比，我们发现报告的MOV10L1多态性与整合到东亚人chr22q端粒中的古代内源性HHV-6A变异体有物理联系。出乎意料的是，hHV-6B变体也已在chr22q中内源化。因此，在该基因座上有两个内源性HHV-6变异体，占日本所有整合的HHV-6的72％。我们还报告了人类基因组仅携带HHV-6B基因组的一部分（即独奏DR），支持体内切除和可能的病毒激活。这些结果共同解释了最近报道的整合的HHV-6与MOV10L1 / piRNA之间的关联，暗示了HHV-6与人类chr22q共同进化的潜在解脱作用，并阐明了唯一完整的（非复古的）进化和重新激活的风险已知存在于人类种系中的病毒基因组。